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Sample records for epigenetic phenotype predetermines

  1. Epigenetic Basis of Morphological Variation and Phenotypic Plasticity in Arabidopsis thaliana

    NARCIS (Netherlands)

    Kooke, R.; Johannes, F.; Wardenaar, R.; Becker, F.F.M.; Etcheverry, M.; Colot, V.; Vreugdenhil, D.; Keurentjes, J.J.B.

    2015-01-01

    Epigenetics is receiving growing attention in the plant science community. Epigenetic modifications are thought to play a particularly important role in fluctuating environments. It is hypothesized that epigenetics contributes to plant phenotypic plasticity because epigenetic modifications, in

  2. Epigenetic variation, phenotypic heritability, and evolution

    DEFF Research Database (Denmark)

    Furrow, Robert E.; Christiansen, Freddy Bugge; Feldman, Marcus W.

    2014-01-01

    families. The potential importance of this interaction, recognized in classical studies of the genetic epidemiology of complex diseases and other quantitative characters, has reemerged in studies of the effects of epigenetic modifications, their variation, and their transmission between generations....

  3. Epigenetic alterations differ in phenotypically distinct human neuroblastoma cell lines

    International Nuclear Information System (INIS)

    Yang, Qiwei; Tian, Yufeng; Ostler, Kelly R; Chlenski, Alexandre; Guerrero, Lisa J; Salwen, Helen R; Godley, Lucy A; Cohn, Susan L

    2010-01-01

    Epigenetic aberrations and a CpG island methylator phenotype have been shown to be associated with poor outcomes in children with neuroblastoma (NB). Seven cancer related genes (THBS-1, CASP8, HIN-1, TIG-1, BLU, SPARC, and HIC-1) that have been shown to have epigenetic changes in adult cancers and play important roles in the regulation of angiogenesis, tumor growth, and apoptosis were analyzed to investigate the role epigenetic alterations play in determining NB phenotype. Two NB cell lines (tumorigenic LA1-55n and non-tumorigenic LA1-5s) that differ in their ability to form colonies in soft agar and tumors in nude mice were used. Quantitative RNA expression analyses were performed on seven genes in LA1-5s, LA1-55n and 5-Aza-dC treated LA1-55n NB cell lines. The methylation status around THBS-1, HIN-1, TIG-1 and CASP8 promoters was examined using methylation specific PCR. Chromatin immunoprecipitation assay was used to examine histone modifications along the THBS-1 promoter. Luciferase assay was used to determine THBS-1 promoter activity. Cell proliferation assay was used to examine the effect of 5-Aza-dC on NB cell growth. The soft agar assay was used to determine the tumorigenicity. Promoter methylation values for THBS-1, HIN-1, TIG-1, and CASP8 were higher in LA1-55n cells compared to LA1-5s cells. Consistent with the promoter methylation status, lower levels of gene expression were detected in the LA1-55n cells. Histone marks associated with repressive chromatin states (H3K9Me3, H3K27Me3, and H3K4Me3) were identified in the THBS-1 promoter region in the LA1-55n cells, but not the LA1-5s cells. In contrast, the three histone codes associated with an active chromatin state (acetyl H3, acetyl H4, and H3K4Me3) were present in the THBS-1 promoter region in LA1-5s cells, but not the LA1-55n cells, suggesting that an accessible chromatin structure is important for THBS-1 expression. We also show that 5-Aza-dC treatment of LA1-55n cells alters the DNA methylation

  4. Epigenetic marks: regulators of livestock phenotypes and conceivable sources of missing variation in livestock improvement programs

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    Eveline M Ibeagha-Awemu

    2015-09-01

    Full Text Available Improvement in animal productivity has been achieved over the years through careful breeding and selection programs. Today, variations in the genome are gaining increasing importance in livestock improvement strategies. Genomic information alone however explains only a part of the phenotypic variance in traits. It is likely that a portion of the unaccounted variance is embedded in the epigenome. The epigenome encompasses epigenetic marks such as DNA methylation, histone tail modifications, chromatin remodeling and other molecules that can transmit epigenetic information such as non-coding RNA species. Epigenetic factors respond to external or internal environmental cues such as nutrition, pathogens and climate, and have the ability to change gene expression leading to emergence of specific phenotypes. Accumulating evidence shows that epigenetic marks influence gene expression and phenotypic outcome in livestock species. This review examines available evidence of the influence of epigenetic marks on livestock (cattle, sheep, goat and pig traits and discusses the potential for consideration of epigenetic markers in livestock improvement programs. However, epigenetic research activities on farm animal species are currently limited partly due to lack of recognition, funding and a global network of researchers. Therefore, considerable less attention has been given to epigenetic research in livestock species in comparison to extensive work in humans and model organisms. Elucidating therefore the epigenetic determinants of animal diseases and complex traits may represent one of the principal challenges to use epigenetic markers for further improvement of animal productivity.

  5. Interpreting phenotypic antibiotic tolerance and persister cells as evolution via epigenetic inheritance.

    Science.gov (United States)

    Day, Troy

    2016-04-01

    Epigenetic inheritance is the transmission of nongenetic material such as gene expression levels, RNA and other biomolecules from parents to offspring. There is a growing realization that such forms of inheritance can play an important role in evolution. Bacteria represent a prime example of epigenetic inheritance because a large array of cellular components is transmitted to offspring, in addition to genetic material. Interestingly, there is an extensive and growing empirical literature showing that many bacteria can form 'persister' cells that are phenotypically resistant or tolerant to antibiotics, but most of these results are not interpreted within the context of epigenetic inheritance. Instead, persister cells are usually viewed as a genetically encoded bet-hedging strategy that has evolved in response to a fluctuating environment. Here I show, using a relatively simple model, that many of these empirical findings can be more simply understood as arising from a combination of epigenetic inheritance and cellular noise. I therefore suggest that phenotypic drug tolerance in bacteria might represent one of the best-studied examples of evolution under epigenetic inheritance. © 2016 John Wiley & Sons Ltd.

  6. Epigenetic reversion of breast carcinoma phenotype is accompaniedby DNA sequestration

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    Sandal, Tone; Valyi-Nagy, Klara; Spencer, Virginia A.; Folberg,Robert; Bissell, Mina J.; Maniotis, Andrew J.

    2006-07-19

    The importance of microenvironment and context in regulation of tissue-specific genes is finally well established. DNA exposure to, or sequestration from, nucleases can be used to detect differences in higher order chromatin structure in intact cells without disturbing cellular or tissue architecture. To investigate the relationship between chromatin organization and tumor phenotype, we utilized an established 3-D assay where normal and malignant human breast cells can be easily distinguished by the morphology of the structures they make (acinus-like vs tumor-like, respectively). We show that these phenotypes can be distinguished also by sensitivity to AluI digestion where the malignant cells are resistant to digestion relative to non-malignant cells. Reversion of the T4-2 breast cancer cells by either cAMP analogs, or a phospatidylinositol 3-kinase (P13K) inhibitor not only reverted the phenotype, but also the chromatin sensitivity to AluI. By using different cAMP-analogs, we show that the cAMP-induced phenotypic reversion, polarization, and shift in DNA organization act through a cAMP-dependent-protein-kinase A-coupled signaling pathway. Importantly, inhibitory antibody to fibronectin also reverted the malignant phenotype, polarized the acini, and changed chromatin sequestration. These experiments show not only that modifying the tumor microenvironment can alter the organization of tumor cells but also that architecture of the tissues and the global chromatin organization are coupled and yet highly plastic.

  7. Extending Injury- and Disease-Resistant CNS Phenotypes by Repetitive Epigenetic Conditioning

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    Jeffrey M. Gidday

    2015-03-01

    Full Text Available Significant reductions in the extent of acute injury in the CNS can be achieved by exposure to different preconditioning stimuli, but the duration of the induced protective phenotype is typically short-lasting, and thus is deemed as limiting its clinical applicability. Extending the period over which such adaptive epigenetic changes persist – in effect, expanding conditioning’s therapeutic window – would significantly broaden the potential applications of such a treatment approach in patients. The frequency of the conditioning stimulus may hold the key. While transient (1-3 days protection against CNS ischemic injury is well established preclinically following a single preconditioning stimulus, repetitively presenting preconditioning stimuli extends the duration of ischemic tolerance by many weeks. Moreover, repetitive intermittent postconditioning enhances postischemic recovery metrics and improves long-term survival. Intermittent conditioning is also efficacious for preventing or delaying injury in preclinical models of chronic neurodegenerative disease, and for promoting long-lasting functional improvements in a number of other pathologies as well. Although the detailed mechanisms underlying these protracted kinds of neuroplasticity remain largely unstudied, accumulating empirical evidence supports the contention that all of these adaptive phenotypes are epigenetically mediated. Going forward, additional preclinical demonstrations of the ability to induce sustained beneficial phenotypes that reduce the burden of acute and chronic neurodegeneration, and experimental interrogations of the regulatory constructs responsible for these epigenetic responses, will accelerate the identification of not only efficacious, but practical, adaptive epigenetics-based treatments for individuals with neurological disease.

  8. Sensitive periods in epigenetics: bringing us closer to complex behavioral phenotypes.

    Science.gov (United States)

    Nagy, Corina; Turecki, Gustavo

    2012-08-01

    Genetic studies have attempted to elucidate causal mechanisms for the development of complex disease, but genome-wide associations have been largely unsuccessful in establishing these links. As an alternative link between genes and disease, recent efforts have focused on mechanisms that alter the function of genes without altering the underlying DNA sequence. Known as epigenetic mechanisms, these include DNA methylation, chromatin conformational changes through histone modifications, ncRNAs and, most recently, 5-hydroxymethylcytosine. Although DNA methylation is involved in normal development, aging and gene regulation, altered methylation patterns have been associated with disease. It is generally believed that early life constitutes a period during which there is increased sensitivity to the regulatory effects of epigenetic mechanisms. The purpose of this review is to outline the contribution of epigenetic mechanisms to genomic function, particularly in the development of complex behavioral phenotypes, focusing on the sensitive periods.

  9. Is Neurofibromatosis Type 1-Noonan Syndrome a Phenotypic Result of Combined Genetic and Epigenetic Factors?

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    Yapijakis, Christos; Pachis, Nikos; Natsis, Stavros; Voumvourakis, Costas

    2016-01-01

    Neurofibromatosis 1-Noonan syndrome (NFNS) presents combined characteristics of both autosomal dominant disorders: NF1 and Noonan syndrome (NS). The genes causing NF1 and NS are located on different chromosomes, making it uncertain whether NFNS is a separate entity as previously suggested, or rather a clinical variation. We present a four-membered Greek family. The father was diagnosed with familial NF1 and the mother with generalized epilepsy, being under hydantoin treatment since the age of 18 years. Their two male children exhibited NFNS characteristics. The father and his sons shared R1947X mutation in the NF1 gene. The two children with NFNS phenotype presented with NF1 signs inherited from their father and fetal hydantoin syndrome-like phenotype due to exposure to that anticonvulsant during fetal development. The NFNS phenotype may be the result of both a genetic factor (mutation in the NF1 gene) and an epigenetic/environmental factor (e.g. hydantoin). Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  10. MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells.

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    Hisataka Ogawa

    Full Text Available Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy. Therefore, cancer reprogramming may be a useful treatment for chemo- or radiotherapy-resistant cancer cells. It was also reported that the introduction of endogenous small-sized, non-coding ribonucleotides such as microRNA (miR 302s and miR-369-3p or -5p resulted in the induction of cellular reprogramming. miRs are smaller than the genes of transcription factors, making them possibly suitable for use in clinical strategies. Therefore, we reprogrammed colon cancer cells using miR-302s and miR-369-3p or -5p. This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells. Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events. Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family. The present study shows that the introduction of miR-302s and miR-369s could induce cellular reprogramming and modulate malignant phenotypes of human colorectal cancer, suggesting that the appropriate delivery of functional small-sized ribonucleotides may open a new avenue for therapy against human malignant tumors.

  11. From genotype to phenotype; clinical variability in Lesch-Nyhan disease. The role of epigenetics.

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    Trigueros Genao, M; Torres, R J

    2014-11-01

    Lesch-Nyhan disease is a rare genetic disease characterized by a deficiency in the function of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Patients affected by this disease experience hyperuricemia, motor disorders, mental retardation and, in the most severe cases, self-mutilation. Its clinical manifestations depend on the enzymatic activity of HGPRT, which is classically linked to the type of alteration in the HGPRT gene. More than 400 mutations of this gene have been found. At present, one of the controversial aspects of the disease is the relationship between the genotype and phenotype; cases have been described lacking a mutation, such as the patient presented in this article, as well as families who despite sharing the same genetic defect show disorders with differing severity. Epigenetic processes, which modify the genetic expression without changing the sequence of the deoxyribonucleic acid (DNA), could explain the clinical variability observed in this disease. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  12. The Importance of ncRNAs as Epigenetic Mechanisms in Phenotypic Variation and Organic Evolution

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    Daniel Frías-Lasserre

    2017-12-01

    Full Text Available Neo-Darwinian explanations of organic evolution have settled on mutation as the principal factor in producing evolutionary novelty. Mechanistic characterizations have been also biased by the classic dogma of molecular biology, where only proteins regulate gene expression. This together with the rearrangement of genetic information, in terms of genes and chromosomes, was considered the cornerstone of evolution at the level of natural populations. This predominant view excluded both alternative explanations and phenomenologies that did not fit its paradigm. With the discovery of non-coding RNAs (ncRNAs and their role in the control of genetic expression, new mechanisms arose providing heuristic power to complementary explanations to evolutionary processes overwhelmed by mainstream genocentric views. Viruses, epimutation, paramutation, splicing, and RNA editing have been revealed as paramount functions in genetic variations, phenotypic plasticity, and diversity. This article discusses how current epigenetic advances on ncRNAs have changed the vision of the mechanisms that generate variation, how organism-environment interaction can no longer be underestimated as a driver of organic evolution, and how it is now part of the transgenerational inheritance and evolution of species.

  13. Epigenetic Editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes.

    NARCIS (Netherlands)

    de Groote, M.L.; Verschure, P.J.; Rots, M.G.

    2012-01-01

    Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined

  14. Epigenetic Editing : targeted rewriting of epigenetic marks to modulate expression of selected target genes

    NARCIS (Netherlands)

    de Groote, Marloes L.; Verschure, Pernette J.; Rots, Marianne G.

    2012-01-01

    Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined

  15. Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming.

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    Wu, Jiazhu; Xu, Xiaojing; Lee, Eun-Joon; Shull, Austin Y; Pei, Lirong; Awan, Farrukh; Wang, Xiaoling; Choi, Jeong-Hyeon; Deng, Libin; Xin, Hong-Bo; Zhong, Wenxun; Liang, Jinhua; Miao, Yi; Wu, Yujie; Fan, Lei; Li, Jianyong; Xu, Wei; Shi, Huidong

    2016-06-28

    Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival. These observations coincided with higher expression of the immune checkpoint receptor PD-1 in CLL patient CD8+ T cells when compared to age-matched healthy donors. Interestingly, we discovered that increased PD-1 expression in CD8+ T cells corresponds with decreased DNA methylation levels in a distal upstream locus of the PD-1 gene PDCD1. Further analysis using luciferase reporter assays suggests that the identified PDCD1 distal upstream region acts as an enhancer for PDCD1 transcription and this region becomes demethylated during activation of naïve CD8+ T cells by anti-CD3/anti-CD28 antibodies and IL2. Finally, we conducted a genome-wide DNA methylation analysis comparing CD8+ T cells from CLL patients against healthy donors and identified additional differentially methylated genes with known immune regulatory functions including CCR6 and KLRG1. Taken together, our findings reveal the occurrence of epigenetic reprogramming taking place within CLL patient CD8+ T cells and highlight the potential mechanism of how immunosuppression is accomplished in CLL.

  16. Advancement of Phenotype Transformation of Cancer-associated Fibroblasts: 
from Genetic Alterations to Epigenetic Modification

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    Dali CHEN

    2015-02-01

    Full Text Available In the field of human cancer research, even though the vast majority attentions were paid to tumor cells as “the seeds”, the roles of tumor microenvironments as “the soil” are gradually explored in recent years. As a dominant compartment of tumor microenvironments, cancer-associated fibroblasts (CAFs were discovered to correlated with tumorigenesis, tumor progression and prognosis. And the exploration of the mechanisms of CAF phenotype transformation would conducive to the further understand of the CAFs function in human cancers. As we known that CAFs have four main origins, including epithelial cells, endothelial cells, mesenchymal stem cells (MSCs and local mesenchymal cells. However, researchers found that all these origins finally conduct similiar phenotypes from intrinsic to extrinsic ones. Thus, what and how a mechanism can conduct the phenotype transformation of CAFs with different origins? Two viewpoints are proposed to try to answer the quetsion, involving genetic alterations and epigenetic modifications. This review will systematically summarize the advancement of mechanisms of CAF phenotype transformations in the aspect of genentic and epigenetic modifications.

  17. Does epigenetic polymorphism contribute to phenotypic variances in Jatropha curcas L.?

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    Bui Ha TN

    2010-11-01

    Full Text Available Abstract Background There is a growing interest in Jatropha curcas L. (jatropha as a biodiesel feedstock plant. Variations in its morphology and seed productivity have been well documented. However, there is the lack of systematic comparative evaluation of distinct collections under same climate and agronomic practices. With the several reports on low genetic diversity in jatropha collections, there is uncertainty on genetic contribution to jatropha morphology. Result In this study, five populations of jatropha plants collected from China (CN, Indonesia (MD, Suriname (SU, Tanzania (AF and India (TN were planted in one farm under the same agronomic practices. Their agronomic traits (branching pattern, height, diameter of canopy, time to first flowering, dormancy, accumulated seed yield and oil content were observed and tracked for two years. Significant variations were found for all the agronomic traits studied. Genetic diversity and epigenetic diversity were evaluated using florescence Amplified Fragment Length Polymorphism (fAFLP and methylation sensitive florescence AFLP (MfAFLP methods. Very low level of genetic diversity was detected (polymorphic band Conclusion Our study confirmed climate and practice independent differences in agronomic performance among jatropha collections. Such agronomic trait variations, however, were matched by very low genetic diversity and medium level but significant epigenetic diversity. Significant difference in inner cytosine and double cytosine methylation at CCGG sites was also found among populations. Most epigenetic differential markers can be inherited as epialleles following Mendelian segregation. These results suggest possible involvement of epigenetics in jatropha development.

  18. Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes

    Science.gov (United States)

    Multhaup, Michael L.; Seldin, Marcus; Jaffe, Andrew E.; Lei, Xia; Kirchner, Henriette; Mondal, Prosenjit; Li, Yuanyuan; Rodriguez, Varenka; Drong, Alexander; Hussain, Mehboob; Lindgren, Cecilia; McCarthy, Mark; Näslund, Erik; Zierath, Juleen R.; Wong, G. William; Feinberg, Andrew P.

    2015-01-01

    SUMMARY Using a functional approach to investigate the epigenetics of Type 2 Diabetes (T2D), we combine three lines of evidence – diet-induced epigenetic dysregulation in mouse, epigenetic conservation in humans, and T2D clinical risk evidence – to identify genes implicated in T2D pathogenesis through epigenetic mechanisms related to obesity. Beginning with dietary manipulation of genetically homogeneous mice, we identify differentially DNA-methylated genomic regions. We then replicate these results in adipose samples from lean and obese patients pre- and post-Roux-en-Y gastric bypass, identifying regions where both the location and direction of methylation change is conserved. These regions overlap with 27 genetic T2D risk loci, only one of which was deemed significant by GWAS alone. Functional analysis of genes associated with these regions revealed four genes with roles in insulin resistance, demonstrating the potential general utility of this approach for complementing conventional human genetic studies by integrating cross-species epigenomics and clinical genetic risk. PMID:25565211

  19. Heterogeneity of chromatin modifications in testicular spermatocytic seminoma point toward an epigenetically unstable phenotype

    DEFF Research Database (Denmark)

    Kristensen, Dina Graae; Mlynarska, Olga; Nielsen, John E

    2012-01-01

    Testicular spermatocytic seminoma (SS) is a rare tumor type predominantly found in elderly men. It is thought to originate from spermatogonia and shows cytological and genetic heterogeneity. In this study, we performed for the first time a comprehensive analysis of epigenetic modifications in a s...

  20. Progression of Tubulointerstitial Fibrosis and the Chronic Kidney Disease Phenotype – Role of Risk Factors and Epigenetics

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    Timothy D. Hewitson

    2017-08-01

    Full Text Available Although the kidney has capacity to repair after mild injury, ongoing or severe damage results in scarring (fibrosis and an associated progressive loss of kidney function. However, despite its universal significance, evidence highlights a population based heterogeneity in the trajectory of chronic kidney disease (CKD in these patients. To explain the heterogeneity of the CKD phenotype requires an understanding of the relevant risk factors for fibrosis. These factors include both the extrinsic nature of injury, and intrinsic factors such as age, gender, genetics, and perpetual activation of fibroblasts through priming. In many cases an additional level of regulation is provided by epigenetic mechanisms which integrate the various pro-fibrotic and anti-fibrotic triggers in fibrogenesis. In this review we therefore examine the various molecular and structural changes of fibrosis, and how they are influenced by extrinsic and intrinsic factors. Our aim is to provide a unifying hypothesis to help explain the transition from acute to CKD.

  1. Genome-wide DNA methylation alterations of Alternanthera philoxeroides in natural and manipulated habitats: implications for epigenetic regulation of rapid responses to environmental fluctuation and phenotypic variation.

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    Gao, Lexuan; Geng, Yupeng; Li, Bo; Chen, Jiakuan; Yang, Ji

    2010-11-01

    Alternanthera philoxeroides (alligator weed) is an invasive weed that can colonize both aquatic and terrestrial habitats. Individuals growing in different habitats exhibit extensive phenotypic variation but little genetic differentiation in its introduced range. The mechanisms underpinning the wide range of phenotypic variation and rapid adaptation to novel and changing environments remain uncharacterized. In this study, we examined the epigenetic variation and its correlation with phenotypic variation in plants exposed to natural and manipulated environmental variability. Genome-wide methylation profiling using methylation-sensitive amplified fragment length polymorphism (MSAP) revealed considerable DNA methylation polymorphisms within and between natural populations. Plants of different source populations not only underwent significant morphological changes in common garden environments, but also underwent a genome-wide epigenetic reprogramming in response to different treatments. Methylation alterations associated with response to different water availability were detected in 78.2% (169/216) of common garden induced polymorphic sites, demonstrating the environmental sensitivity and flexibility of the epigenetic regulatory system. These data provide evidence of the correlation between epigenetic reprogramming and the reversible phenotypic response of alligator weed to particular environmental factors. © 2010 Blackwell Publishing Ltd.

  2. Genetic and Epigenetic Tumor Suppressor Gene Silencing are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Non small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Marsit, C. J.; Kelsey, K. T.; Houseman, E. A.; Kelsey, K. T.; Houseman, E. A.; Nelson, H. H.

    2008-01-01

    Both genetic and epigenetic alterations characterize human non small cell lung cancer (NSCLC), but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hyper methylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hyper methylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hyper methylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hyper methylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

  3. Genetic and Epigenetic Tumor Suppressor Gene Silencing Are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Nonsmall Cell Lung Cancer

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    Carmen J. Marsit

    2008-01-01

    Full Text Available Both genetic and epigenetic alterations characterize human nonsmall cell lung cancer (NSCLC, but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hypermethylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hypermethylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hypermethylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hypermethylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

  4. Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition.

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    Heo, Hye J; Tozour, Jessica N; Delahaye, Fabien; Zhao, Yongmei; Cui, Lingguang; Barzilai, Nir; Einstein, Francine Hughes

    2016-10-01

    Adverse environmental exposures of mothers during fetal period predispose offspring to a range of age-related diseases earlier in life. Here, we set to determine whether a deregulated epigenetic pattern is similar in young animals whose mothers' nutrition was modulated during fetal growth to that acquired during normal aging in animals. Using a rodent model of maternal undernutrition (UN) or overnutrition (ON), we examined cytosine methylation profiles of liver from young female offspring and compared them to age-matched young controls and aged (20-month-old) animals. HELP-tagging, a genomewide restriction enzyme and sequencing assay demonstrates that fetal exposure to two different maternal diets is associated with nonrandom dysregulation of methylation levels with profiles similar to those seen in normal aging animals and occur in regions mapped to genes relevant to metabolic diseases and aging. Functional consequences were assessed by gene expression at 9 weeks old with more significant changes at 6 months of age. Early developmental exposures to unfavorable maternal diets result in altered methylation profiles and transcriptional dysregulation in Prkcb, Pc, Ncor2, and Smad3 that is also seen with normal aging. These Notch pathway and lipogenesis genes may be useful for prediction of later susceptibility to chronic disease. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  5. 17 CFR 8.10 - Predetermined penalties.

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    2010-04-01

    ... Section 8.10 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION EXCHANGE PROCEDURES FOR DISCIPLINARY, SUMMARY, AND MEMBERSHIP DENIAL ACTIONS Disciplinary Procedure § 8.10 Predetermined... the rules of an exchange establish predetermined penalties, the disciplinary committee shall have...

  6. Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas.

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    Marta M Alonso

    Full Text Available We undertook this study to understand how the transcription factor Sox2 contributes to the malignant phenotype of glioblastoma multiforme (GBM, the most aggressive primary brain tumor. We initially looked for unbalanced genomic rearrangements in the Sox2 locus in 42 GBM samples and found that Sox2 was amplified in 11.5% and overexpressed in all the samples. These results prompted us to further investigate the mechanisms involved in Sox2 overexpression in GBM. We analyzed the methylation status of the Sox2 promoter because high CpG density promoters are associated with key developmental genes. The Sox2 promoter presented a CpG island that was hypomethylated in all the patient samples when compared to normal cell lines. Treatment of Sox2-negative glioma cell lines with 5-azacitidine resulted in the re-expression of Sox2 and in a change in the methylation status of the Sox2 promoter. We further confirmed these results by analyzing data from GBM cases generated by The Cancer Genome Atlas project. We observed Sox2 overexpression (86%; N = 414, Sox2 gene amplification (8.5%; N = 492, and Sox 2 promoter hypomethylation (100%; N = 258, suggesting the relevance of this factor in the malignant phenotype of GBMs. To further explore the role of Sox2, we performed in vitro analysis with brain tumor stem cells (BTSCs and established glioma cell lines. Downmodulation of Sox2 in BTSCs resulted in the loss of their self-renewal properties. Surprisingly, ectopic expression of Sox2 in established glioma cells was not sufficient to support self-renewal, suggesting that additional factors are required. Furthermore, we observed that ectopic Sox2 expression was sufficient to induce invasion and migration of glioma cells, and knockdown experiments demonstrated that Sox2 was essential for maintaining these properties. Altogether, our data underscore the importance of a pleiotropic role of Sox2 and suggest that it could be used as a therapeutic target in GBM.

  7. SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation.

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    Tomohisa Hayakawa

    Full Text Available Senescent cells develop a pro-inflammatory response termed the senescence-associated secretory phenotype (SASP. As many SASP components affect surrounding cells and alter their microenvironment, SASP may be a key phenomenon in linking cellular senesence with individual aging and age-related diseases. We herein demonstrated that the expression of Sirtuin1 (SIRT1 was decreased and the expression of SASP components was reciprocally increased during cellular senescence. The mRNAs and proteins of SASP components, such as IL-6 and IL-8, quickly accumulated in SIRT1-depleted cells, and the levels of these factors were also higher than those in control cells, indicating that SIRT1 negatively regulated the expression of SASP factors at the transcriptional level. SIRT1 bound to the promoter regions of IL-8 and IL-6, but dissociated from them during cellular senescence. The acetylation of Histone H3 (K9 and H4 (K16 of the IL-8 and IL-6 promoter regions gradually increased during cellular senescence. In SIRT1-depleted cells, the acetylation levels of these regions were already higher than those in control cells in the pre-senescent stage. Moreover, these acetylation levels in SIRT1-depleted cells were significantly higher than those in control cells during cellular senescence. These results suggest that SIRT1 repressed the expression of SASP factors through the deacetylation of histones in their promoter regions.

  8. Epigenetic and phenotypic profile of fibroblasts derived from induced pluripotent stem cells.

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    Kyle J Hewitt

    2011-02-01

    Full Text Available Human induced pluripotent stem (hiPS cells offer a novel source of patient-specific cells for regenerative medicine. However, the biological potential of iPS-derived cells and their similarities to cells differentiated from human embryonic stem (hES cells remain unclear. We derived fibroblast-like cells from two hiPS cell lines and show that their phenotypic properties and patterns of DNA methylation were similar to that of mature fibroblasts and to fibroblasts derived from hES cells. iPS-derived fibroblasts (iPDK and their hES-derived counterparts (EDK showed similar cell morphology throughout differentiation, and patterns of gene expression and cell surface markers were characteristic of mature fibroblasts. Array-based methylation analysis was performed for EDK, iPDK and their parental hES and iPS cell lines, and hierarchical clustering revealed that EDK and iPDK had closely-related methylation profiles. DNA methylation analysis of promoter regions associated with extracellular matrix (ECM-production (COL1A1 by iPS- and hESC-derived fibroblasts and fibroblast lineage commitment (PDGFRβ, revealed promoter demethylation linked to their expression, and patterns of transcription and methylation of genes related to the functional properties of mature stromal cells were seen in both hiPS- and hES-derived fibroblasts. iPDK cells also showed functional properties analogous to those of hES-derived and mature fibroblasts, as seen by their capacity to direct the morphogenesis of engineered human skin equivalents. Characterization of the functional behavior of ES- and iPS-derived fibroblasts in engineered 3D tissues demonstrates the utility of this tissue platform to predict the capacity of iPS-derived cells before their therapeutic application.

  9. Depletion of tumor-associated macrophages switches the epigenetic profile of pancreatic cancer infiltrating T cells and restores their anti-tumor phenotype.

    Science.gov (United States)

    Borgoni, Simone; Iannello, Andrea; Cutrupi, Santina; Allavena, Paola; D'Incalci, Maurizio; Novelli, Francesco; Cappello, Paola

    2018-01-01

    Pancreatic Ductal Adenocarcinoma (PDA) is characterized by a complex tumor microenvironment that supports its progression, aggressiveness and resistance to therapies. The delicate interplay between cancer and immune cells creates the conditions for PDA development, particularly due to the functional suppression of T cell anti-tumor effector activity. However, some of the mechanisms involved in this process are still poorly understood. In this study, we analyze whether the functional and epigenetic profile of T cells that infiltrate PDA is modulated by the microenvironment, and in particular by tumor-associated macrophages (TAMs). CD4 and CD8 T cells obtained from mice orthotopically injected with syngeneic PDA cells, and untreated or treated with Trabectedin, a cytotoxic drug that specifically targets TAMs, were sorted and analyzed by flow cytometry and characterized for their epigenetic profile. Assessment of cytokine production and the epigenetic profile of genes coding for IL10, T-bet and PD1 revealed that T cells that infiltrated PDA displayed activated Il10 promoter and repressed T-bet activity, in agreement with their regulatory phenotype (IL10 high /IFNγ low , PD1 high ). By contrast, in Trabectedin-treated mice, PDA-infiltrating T cells displayed repressed Il10 and Pdcd1 and activated T-bet promoter activity, in accordance with their anti-tumor effector phenotype (IL10 low /IFNγ high ), indicating a key role of TAMs in orchestrating functions of PDA-infiltrating T cells by modulating their epigenetic profile towards a pro-tumoral phenotype. These results suggest the targeting of TAMs as an efficient strategy to obtain an appropriate T cell anti-tumor immune response and open new potential combinations for PDA treatment.

  10. Molecular characterization of a rice mutator-phenotype derived from an incompatible cross-pollination reveals transgenerational mobilization of multiple transposable elements and extensive epigenetic instability

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    Xu Chunming

    2009-05-01

    Full Text Available Abstract Background Inter-specific hybridization occurs frequently in plants, which may induce genetic and epigenetic instabilities in the resultant hybrids, allopolyploids and introgressants. It remains unclear however whether pollination by alien pollens of an incompatible species may impose a "biological stress" even in the absence of genome-merger or genetic introgression, whereby genetic and/or epigenetic instability of the maternal recipient genome might be provoked. Results We report here the identification of a rice mutator-phenotype from a set of rice plants derived from a crossing experiment involving two remote and apparently incompatible species, Oryza sativa L. and Oenothera biennis L. The mutator-phenotype (named Tong211-LP showed distinct alteration in several traits, with the most striking being substantially enlarged panicles. Expectably, gel-blotting by total genomic DNA of the pollen-donor showed no evidence for introgression. Characterization of Tong211-LP (S0 and its selfed progenies (S1 ruled out contamination (via seed or pollen or polyploidy as a cause for its dramatic phenotypic changes, but revealed transgenerational mobilization of several previously characterized transposable elements (TEs, including a MITE (mPing, and three LTR retrotransposons (Osr7, Osr23 and Tos17. AFLP and MSAP fingerprinting revealed extensive, transgenerational alterations in cytosine methylation and to a less extent also genetic variation in Tong211-LP and its immediate progenies. mPing mobility was found to correlate with cytosine methylation alteration detected by MSAP but not with genetic variation detected by AFLP. Assay by q-RT-PCR of the steady-state transcript abundance of a set of genes encoding for the various putative DNA methyltransferases, 5-methylcytosine DNA glycosylases, and small interference RNA (siRNA pathway-related proteins showed that, relative to the rice parental line, heritable perturbation in expression of 12 out of

  11. Epigenetics: ambiguities and implications.

    Science.gov (United States)

    Stotz, Karola; Griffiths, Paul

    2016-12-01

    Everyone has heard of 'epigenetics', but the term means different things to different researchers. Four important contemporary meanings are outlined in this paper. Epigenetics in its various senses has implications for development, heredity, and evolution, and also for medicine. Concerning development, it cements the vision of a reactive genome strongly coupled to its environment. Concerning heredity, both narrowly epigenetic and broader 'exogenetic' systems of inheritance play important roles in the construction of phenotypes. A thoroughly epigenetic model of development and evolution was Waddington's aim when he introduced the term 'epigenetics' in the 1940s, but it has taken the modern development of molecular epigenetics to realize this aim. In the final sections of the paper we briefly outline some further implications of epigenetics for medicine and for the nature/nurture debate.

  12. Epigenetic considerations in aquaculture

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    Mackenzie R. Gavery

    2017-12-01

    Full Text Available Epigenetics has attracted considerable attention with respect to its potential value in many areas of agricultural production, particularly under conditions where the environment can be manipulated or natural variation exists. Here we introduce key concepts and definitions of epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNA, review the current understanding of epigenetics in both fish and shellfish, and propose key areas of aquaculture where epigenetics could be applied. The first key area is environmental manipulation, where the intention is to induce an ‘epigenetic memory’ either within or between generations to produce a desired phenotype. The second key area is epigenetic selection, which, alone or combined with genetic selection, may increase the reliability of producing animals with desired phenotypes. Based on aspects of life history and husbandry practices in aquaculture species, the application of epigenetic knowledge could significantly affect the productivity and sustainability of aquaculture practices. Conversely, clarifying the role of epigenetic mechanisms in aquaculture species may upend traditional assumptions about selection practices. Ultimately, there are still many unanswered questions regarding how epigenetic mechanisms might be leveraged in aquaculture.

  13. [Multiple coronary arteriovenous fistulae. Hazard or predetermination?].

    Science.gov (United States)

    Rangel, Alberto; Muñoz-Castellanos, Luis; Solorio, Sergio

    2003-01-01

    The authors present the clinical cases of three adult patients (49, 53 and 61 year-old), with rheumatic cardiac valvulopathy, and bilateral coronary arteriovenous fistulae draining in the main pulmonary artery. Based on documental investigation, the authors speculate about the predeterminate origin of coronary arteriovenous fistulae. At first glance, it seems obvious that congenital cardiopathies occur at random, i.e., embryonic development deviate or stops due to unknown reasons, originating the persistence of lacunar blood spaces prior to the development of coronary arteries cords. There are two factors involved in the genesis of congenital malformations: a genomic preexisting factor and the presence of an environmental precipitating factor, i.e., isolated pulmonary valve atresia or left ventricular hypoplastic syndrome, with mitral and aortic valve stenosis, can predispose development of coronary arteriovenous fistulae. Recently, the question has been raised whether there is a relation of coronary arteries fistulae with: ethnic groups, hereditary gigantism, autoimmune diseases, such as polymyositis, hereditary hemorrhagic telangiectasia, and apical hypertrophic myocardiopathy. Coronary arteriovenous fistulae, as well as some congenital cardiopathies, could be due to chromosome alterations or might be related to hereditary diseases, such as hemorrhagic telangiectasia, induced by a disturbed genetic program. Although, there is no concrete evidence that a genetic factor is related to the development of coronary arteriovenous fistulae, there are signs that suggest that such a possibility could be investigated.

  14. Epigenetics in natural animal populations.

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    Hu, J; Barrett, R D H

    2017-09-01

    Phenotypic plasticity is an important mechanism for populations to buffer themselves from environmental change. While it has long been appreciated that natural populations possess genetic variation in the extent of plasticity, a surge of recent evidence suggests that epigenetic variation could also play an important role in shaping phenotypic responses. Compared with genetic variation, epigenetic variation is more likely to have higher spontaneous rates of mutation and a more sensitive reaction to environmental inputs. In our review, we first provide an overview of recent studies on epigenetically encoded thermal plasticity in animals to illustrate environmentally-mediated epigenetic effects within and across generations. Second, we discuss the role of epigenetic effects during adaptation by exploring population epigenetics in natural animal populations. Finally, we evaluate the evolutionary potential of epigenetic variation depending on its autonomy from genetic variation and its transgenerational stability. Although many of the causal links between epigenetic variation and phenotypic plasticity remain elusive, new data has explored the role of epigenetic variation in facilitating evolution in natural populations. This recent progress in ecological epigenetics will be helpful for generating predictive models of the capacity of organisms to adapt to changing climates. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  15. Epigenetic up-regulation of ribosome biogenesis and more aggressive phenotype triggered by the lack of the histone demethylase JHDM1B in mammary epithelial cells.

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    Galbiati, Alice; Penzo, Marianna; Bacalini, Maria Giulia; Onofrillo, Carmine; Guerrieri, Ania Naila; Garagnani, Paolo; Franceschi, Claudio; Treré, Davide; Montanaro, Lorenzo

    2017-06-06

    The alterations of ribosome biogenesis and protein synthesis play a direct role in the development of tumors. The accessibility and transcription of ribosomal genes is controlled at several levels, with their epigenetic regulation being one of the most important. Here we explored the JmjC domain-containing histone demethylase 1B (JHDM1B) function in the epigenetic control of rDNA transcription. Since JHDM1B is a negative regulator of gene transcription, we focused on the effects induced by JHDM1B knock-down (KD). We studied the consequences of stable inducible JHDM1B silencing in cell lines derived from transformed and untransformed mammary epithelial cells. In these cellular models, prolonged JHDM1B downregulation triggered a surge of 45S pre-rRNA transcription and processing, associated with a re-modulation of the H3K36me2 levels at rDNA loci and with changes in DNA methylation of specific CpG sites in rDNA genes. We also found that after JHDM1B KD, cells showed a higher ribosome content: which were engaged in mRNA translation. JHDM1B KD and the consequent stimulation of ribosomes biogenesis conferred more aggressive features to the tested cellular models, which acquired a greater clonogenic, staminal and invasive potential. Taken together, these data indicate that the reduction of JHDM1B leads to a more aggressive cellular phenotype in mammary gland cells, by virtue of its negative regulatory activity on ribosome biogenesis.

  16. Epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS)-like phenotypes in prenatally androgenized rhesus monkeys.

    Science.gov (United States)

    Xu, Ning; Kwon, Soonil; Abbott, David H; Geller, David H; Dumesic, Daniel A; Azziz, Ricardo; Guo, Xiuqing; Goodarzi, Mark O

    2011-01-01

    The pathogenesis of polycystic ovary syndrome (PCOS) is poorly understood. PCOS-like phenotypes are produced by prenatal androgenization (PA) of female rhesus monkeys. We hypothesize that perturbation of the epigenome, through altered DNA methylation, is one of the mechanisms whereby PA reprograms monkeys to develop PCOS. Infant and adult visceral adipose tissues (VAT) harvested from 15 PA and 10 control monkeys were studied. Bisulfite treated samples were subjected to genome-wide CpG methylation analysis, designed to simultaneously measure methylation levels at 27,578 CpG sites. Analysis was carried out using Bayesian Classification with Singular Value Decomposition (BCSVD), testing all probes simultaneously in a single test. Stringent criteria were then applied to filter out invalid probes due to sequence dissimilarities between human probes and monkey DNA, and then mapped to the rhesus genome. This yielded differentially methylated loci between PA and control monkeys, 163 in infant VAT, and 325 in adult VAT (BCSVD Pexcess fetal androgen exposure in female nonhuman primates may predispose to PCOS via alteration of the epigenome, providing a novel avenue to understand PCOS in humans.

  17. Epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS-like phenotypes in prenatally androgenized rhesus monkeys.

    Directory of Open Access Journals (Sweden)

    Ning Xu

    Full Text Available The pathogenesis of polycystic ovary syndrome (PCOS is poorly understood. PCOS-like phenotypes are produced by prenatal androgenization (PA of female rhesus monkeys. We hypothesize that perturbation of the epigenome, through altered DNA methylation, is one of the mechanisms whereby PA reprograms monkeys to develop PCOS. Infant and adult visceral adipose tissues (VAT harvested from 15 PA and 10 control monkeys were studied. Bisulfite treated samples were subjected to genome-wide CpG methylation analysis, designed to simultaneously measure methylation levels at 27,578 CpG sites. Analysis was carried out using Bayesian Classification with Singular Value Decomposition (BCSVD, testing all probes simultaneously in a single test. Stringent criteria were then applied to filter out invalid probes due to sequence dissimilarities between human probes and monkey DNA, and then mapped to the rhesus genome. This yielded differentially methylated loci between PA and control monkeys, 163 in infant VAT, and 325 in adult VAT (BCSVD P<0.05. Among these two sets of genes, we identified several significant pathways, including the antiproliferative role of TOB in T cell signaling and transforming growth factor-β (TGF-β signaling. Our results suggest PA may modify DNA methylation patterns in both infant and adult VAT. This pilot study suggests that excess fetal androgen exposure in female nonhuman primates may predispose to PCOS via alteration of the epigenome, providing a novel avenue to understand PCOS in humans.

  18. Fatty acid binding protein 3 (fabp3) is associated with insulin, lipids and cardiovascular phenotypes of the metabolic syndrome through epigenetic modifications in a Northern European family population.

    Science.gov (United States)

    Zhang, Yi; Kent, Jack W; Lee, Adam; Cerjak, Diana; Ali, Omar; Diasio, Robert; Olivier, Michael; Blangero, John; Carless, Melanie A; Kissebah, Ahmed H

    2013-03-19

    Fatty acid-binding proteins (FABPs) play regulatory roles at the nexus of lipid metabolism and signaling. Dyslipidemia in clinical manifestation frequently co-occurs with obesity, insulin resistance and hypertension in the Metabolic Syndrome (MetS). Animal studies have suggested FABPs play regulatory roles in expressing MetS phenotypes. In our family cohort of Northern European descent, transcript levels in peripheral white blood cells (PWBCs) of a key FABPs, FABP3, is correlated with the MetS leading components. However, evidence supporting the functions of FABPs in humans using genetic approaches has been scarce, suggesting FABPs may be under epigenetic regulation. The objective of this study was to test the hypothesis that CpG methylation status of a key regulator of lipid homeostasis, FABP3, is a quantitative trait associated with status of MetS phenotypes in humans. We used a mass-spec based quantitative method, EpiTYPER®, to profile a CpG island that extends from the promoter to the first exon of the FABP3 gene in our family-based cohort of Northern European descent (n=517). We then conducted statistical analysis of the quantitative relationship of CpG methylation and MetS measures following the variance-component association model. Heritability of each methylation and the effect of age and sex on CpG methylation were also assessed in our families. We find that methylation levels of individual CpG units and the regional average are heritable and significantly influenced by age and sex. Regional methylation was strongly associated with plasma total cholesterol (p=0.00028) and suggestively associated with LDL-cholesterol (p=0.00495). Methylation at individual units was significantly associated with insulin sensitivity, lipid particle sizing and diastolic blood pressure (pmetabolism (βWHR=-0.72; βLDL-c=-0.53) while positively correlated with plasma adiponectin (β=0.24). Further, we show that differential methylation of FABP3 affects binding activity with

  19. Epigenetic regulation in obesity.

    Science.gov (United States)

    Drummond, Elaine M; Gibney, Eileen R

    2013-07-01

    Research suggests that 65% of variation in obesity is genetic. However, much of the known genetic associations have little known function and their effect size small, thus the gene-environment interaction, including epigenetic influences on gene expression, is suggested to be an important factor in the susceptibilty to obesity. This review will explore the potential of epigenetic markers to influence expression of genes associated with obesity. Epigenetic changes in utero are known to have direct implications on the phenotype of the offspring. More recently work has focused on how such epigenetic changes continue to regulate risk of obesity from infancy through to adulthood. Work has shown that, for example, hypomethylation of the MC4 gene causes an increase in expression, and has a direct impact on appetite and intake, and thus influences risk of obesity. Similar influences are also seen in other aspects of obesity including inflammation and adiposity. Maternal diet during foetal development has many epigenetic implications, which affect the offspring's risk factors for obesity during childhood and adulthood, and even in subsequent generations. Genes associated with risk of obesity, are susceptible to epigenetic mutations, which have subsequent effects on disease mechanisms, such as appetite and impaired glucose and insulin tolerance.

  20. Epigenetics: What it is about?

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    Saade E.

    2014-01-01

    Full Text Available Epigenetics has captured the attention of scientists in the past decades, yet its scope has been continuously changing. In this paper, we give an overview on how and why its definition has evolved and suggest several clarification on the concepts used in this field. Waddington coined the term in 1942 to describe genes interaction with each other and with their environment and insisted on dissociating these events from development. Then, Holliday and others argued that epigenetic phenomena are characterized by their heritability. However, differentiated cells can maintain their phenotypes for decades without undergoing division, which points out the limitation of the «heritability» criterion for a particular phenomenon to qualify as epigenetic. «Epigenetic stability» encompasses traits preservation in both dividing and non dividing cells. Likewise, the use of the term «epigenetic regulation» has been misleading as it overlaps with «regulation of gene expression», whereas «epigenetic information» clearly distinguishes epigenetic from genetic phenomena. Consequently, how could epigenetic information be transmitted and perpetuated? The term «epigenetic templating» has been proposed to refer to a general mechanism of perpetuation of epigenetic information that is based on the preferential activity of enzymes that deposit a particular epigenetic mark on macromolecular complexes already containing the same mark. Another issue that we address is the role of epigenetic information. Not only it is important in allowing alternative interpretations of genetic information, but it appears to be important in protecting the genome, as can be illustrated by bacterial endonucleases that targets non methylated DNA – i. e. foreign DNA – and not the endogenous methylated DNA.

  1. Nutritional epigenetics

    Science.gov (United States)

    This chapter is intended to provide a timely overview of the current state of research at the intersection of nutrition and epigenetics. I begin by describing epigenetics and molecular mechanisms of eigenetic regulation, then highlight four classes of nutritional exposures currently being investiga...

  2. Epigenetic rejuvenation.

    Science.gov (United States)

    Manukyan, Maria; Singh, Prim B

    2012-05-01

    Induced pluripotent stem (iPS) cells have provided a rational means of obtaining histo-compatible tissues for 'patient-specific' regenerative therapies (Hanna et al. 2010; Yamanaka & Blau 2010). Despite the obvious potential of iPS cell-based therapies, there are certain problems that must be overcome before these therapies can become safe and routine (Ohi et al. 2011; Pera 2011). As an alternative, we have recently explored the possibility of using 'epigenetic rejuvenation', where the specialized functions of an old cell are rejuvenated in the absence of any change in its differentiated state (Singh & Zacouto 2010). The mechanism(s) that underpin 'epigenetic rejuvenation' are unknown and here we discuss model systems, using key epigenetic modifiers, which might shed light on the processes involved. Epigenetic rejuvenation has advantages over iPS cell techniques that are currently being pursued. First, the genetic and epigenetic abnormalities that arise through the cycle of dedifferentiation of somatic cells to iPS cells followed by redifferentiation of iPS cells into the desired cell type are avoided (Gore et al. 2011; Hussein et al. 2011; Pera 2011): epigenetic rejuvenation does not require passage through the de-/redifferentiation cycle. Second, because the aim of epigenetic rejuvenation is to ensure that the differentiated cell type retains its specialized function it makes redundant the question of transcriptional memory that is inimical to iPS cell-based therapies (Ohi et al. 2011). Third, to produce unrelated cell types using the iPS technology takes a long time, around three weeks, whereas epigenetic rejuvenation of old cells will take only a matter of days. Epigenetic rejuvenation provides the most safe, rapid and cheap route to successful regenerative medicine. © 2012 The Authors. Journal compilation © 2012 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

  3. Epigenetics and environmental impacts in cattle

    Science.gov (United States)

    This chapter reviews the major advances in the field of epigenetics as well as the environmental impacts of cattle. Many findings from our own research endeavors related to the topic of this chapter are also introduced. The phenotypic characterization of an animal can be changed through epigenetic ...

  4. Epigenetics and Colorectal Cancer

    Science.gov (United States)

    Lao, Victoria Valinluck; Grady, William M.

    2012-01-01

    Colorectal cancer is a leading cause of cancer deaths in the world. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells that transforms them into adenocarcinomas. There have been major advances in our understanding of cancer epigenetics over the last decade, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all colorectal cancers have aberrantly methylated genes and the average colorectal cancer methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to play a functional role in colorectal cancer. The assessment of methylated genes in colorectal cancers has also revealed a unique molecular subgroup of colorectal cancers called CpG Island Methylator Phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. The advances in our understanding of aberrant methylation in colorectal cancer has led to epigenetic alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in the assessment of epigenetic alterations in colorectal cancer and their clinical applications has shown that these alterations will be commonly used in the near future as molecular markers to direct the prevention and treatment of colorectal cancer. PMID:22009203

  5. Twin methodology in epigenetic studies

    DEFF Research Database (Denmark)

    Tan, Qihua; Christiansen, Lene; von Bornemann Hjelmborg, Jacob

    2015-01-01

    of diseases to molecular phenotypes in functional genomics especially in epigenetics, a thriving field of research that concerns the environmental regulation of gene expression through DNA methylation, histone modification, microRNA and long non-coding RNA expression, etc. The application of the twin method...

  6. The Emerging Role of Epigenetics in Inflammation and Immunometabolism

    DEFF Research Database (Denmark)

    Raghuraman, Sukanya; Donkin, Ida; Versteyhe, Soetkin

    2016-01-01

    Recent research developments have shed light on the risk factors contributing to metabolic complications, implicating both genetic and environmental factors, potentially integrated by epigenetic mechanisms. Distinct epigenetic changes in immune cells are frequently observed in obesity and type 2 ...... we provide an overview of the epigenetic mechanisms influencing immune cell phenotype and function, summarize current knowledge about epigenetic changes affecting immune functions in the context of metabolic diseases, and discuss the therapeutic options currently available to counteract...

  7. Behavioral epigenetics.

    Science.gov (United States)

    Moore, David S

    2017-01-01

    Why do we grow up to have the traits we do? Most 20th century scientists answered this question by referring only to our genes and our environments. But recent discoveries in the emerging field of behavioral epigenetics have revealed factors at the interface between genes and environments that also play crucial roles in development. These factors affect how genes work; scientists now know that what matters as much as which genes you have (and what environments you encounter) is how your genes are affected by their contexts. The discovery that what our genes do depends in part on our experiences has shed light on how Nature and Nurture interact at the molecular level inside of our bodies. Data emerging from the world's behavioral epigenetics laboratories support the idea that a person's genes alone cannot determine if, for example, he or she will end up shy, suffering from cardiovascular disease, or extremely smart. Among the environmental factors that can influence genetic activity are parenting styles, diets, and social statuses. In addition to influencing how doctors treat diseases, discoveries about behavioral epigenetics are likely to alter how biologists think about evolution, because some epigenetic effects of experience appear to be transmissible from generation to generation. This domain of research will likely change how we think about the origins of human nature. WIREs Syst Biol Med 2017, 9:e1333. doi: 10.1002/wsbm.1333 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

  8. Nucleosome Positioning and Epigenetics

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    Schwab, David; Bruinsma, Robijn

    2008-03-01

    The role of chromatin structure in gene regulation has recently taken center stage in the field of epigenetics, phenomena that change the phenotype without changing the DNA sequence. Recent work has also shown that nucleosomes, a complex of DNA wrapped around a histone octamer, experience a sequence dependent energy landscape due to the variation in DNA bend stiffness with sequence composition. In this talk, we consider the role nucleosome positioning might play in the formation of heterochromatin, a compact form of DNA generically responsible for gene silencing. In particular, we discuss how different patterns of nucleosome positions, periodic or random, could either facilitate or suppress heterochromatin stability and formation.

  9. Nonlinear Epigenetic Variance: Review and Simulations

    Science.gov (United States)

    Kan, Kees-Jan; Ploeger, Annemie; Raijmakers, Maartje E. J.; Dolan, Conor V.; van Der Maas, Han L. J.

    2010-01-01

    We present a review of empirical evidence that suggests that a substantial portion of phenotypic variance is due to nonlinear (epigenetic) processes during ontogenesis. The role of such processes as a source of phenotypic variance in human behaviour genetic studies is not fully appreciated. In addition to our review, we present simulation studies…

  10. The epigenetic footprint of poleward range-expanding plants in apomictic dandelions

    NARCIS (Netherlands)

    Preite, V.; Snoek, L.B.; Oplaat, C.; Biere, A.; Putten, van der W.H.; Verhoeven, K.J.F.

    2015-01-01

    Epigenetic modifications, such as DNA methylation variation, can generate heritable phenotypic variation independent of the underlying genetic code. However, epigenetic variation in natural plant populations is poorly documented and little understood. Here, we test if northward range expansion of

  11. Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types

    DEFF Research Database (Denmark)

    Ecker, Simone; Chen, Lu; Pancaldi, Vera

    2017-01-01

    Background: A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability. Results: We apply a novel analytical approach to measure and compare transcriptional and epigenetic v...

  12. Long-Term Effects of the Periconception Period on Embryo Epigenetic Profile and Phenotype: The Role of Stress and How This Effect Is Mediated.

    Science.gov (United States)

    Ord, James; Fazeli, Alireza; Watt, Penelope J

    2017-01-01

    Stress represents an unavoidable aspect of human life, and pathologies associated with dysregulation of stress mechanisms - particularly psychiatric disorders - represent a significant global health problem. While it has long been observed that levels of stress experienced in the periconception period may greatly affect the offspring's risk of psychiatric disorders, the mechanisms underlying these associations are not yet comprehensively understood. In order to address this question, this chapter will take a 'top-down' approach, by first defining stress and associated concepts, before exploring the mechanistic basis of the stress response in the form of the hypothalamic-pituitary-adrenal (HPA) axis, and how dysregulation of the HPA axis can impede our mental and physical health, primarily via imbalances in glucocorticoids (GCs) and their corresponding receptors (GRs) in the brain. The current extent of knowledge pertaining to the impact of stress on developmental programming and epigenetic inheritance is then extensively discussed, including the role of chromatin remodelling associated with specific HPA axis-related genes and the possible role of regulatory RNAs as messengers of environmental stress both in the intrauterine environment and across the germ line. Furthering our understanding of the role of stress on embryonic development is crucial if we are to increase our predictive power of disease risk and devise-effective treatments and intervention strategies.

  13. Epigenetic Effect of Environmental Factors on Autism Spectrum Disorders

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    Takeo Kubota

    2016-05-01

    Full Text Available Both environmental factors and genetic factors are involved in the pathogenesis of autism spectrum disorders (ASDs. Epigenetics, an essential mechanism for gene regulation based on chemical modifications of DNA and histone proteins, is also involved in congenital ASDs. It was recently demonstrated that environmental factors, such as endocrine disrupting chemicals and mental stress in early life, can change epigenetic status and gene expression, and can cause ASDs. Moreover, environmentally induced epigenetic changes are not erased during gametogenesis and are transmitted to subsequent generations, leading to changes in behavior phenotypes. However, epigenetics has a reversible nature since it is based on the addition or removal of chemical residues, and thus the original epigenetic status may be restored. Indeed, several antidepressants and anticonvulsants used for mental disorders including ASDs restore the epigenetic state and gene expression. Therefore, further epigenetic understanding of ASDs is important for the development of new drugs that take advantages of epigenetic reversibility.

  14. Epigenetic Effect of Environmental Factors on Autism Spectrum Disorders.

    Science.gov (United States)

    Kubota, Takeo; Mochizuki, Kazuki

    2016-05-14

    Both environmental factors and genetic factors are involved in the pathogenesis of autism spectrum disorders (ASDs). Epigenetics, an essential mechanism for gene regulation based on chemical modifications of DNA and histone proteins, is also involved in congenital ASDs. It was recently demonstrated that environmental factors, such as endocrine disrupting chemicals and mental stress in early life, can change epigenetic status and gene expression, and can cause ASDs. Moreover, environmentally induced epigenetic changes are not erased during gametogenesis and are transmitted to subsequent generations, leading to changes in behavior phenotypes. However, epigenetics has a reversible nature since it is based on the addition or removal of chemical residues, and thus the original epigenetic status may be restored. Indeed, several antidepressants and anticonvulsants used for mental disorders including ASDs restore the epigenetic state and gene expression. Therefore, further epigenetic understanding of ASDs is important for the development of new drugs that take advantages of epigenetic reversibility.

  15. Epigenetic Inheritance Across the Landscape

    Directory of Open Access Journals (Sweden)

    Amy Vaughn Whipple

    2016-10-01

    Full Text Available The study of epigenomic variation at the landscape-level in plants may add important insight to studies of adaptive variation. A major goal of landscape genomic studies is to identify genomic regions contributing to adaptive variation across the landscape. Heritable variation in epigenetic marks, resulting in transgenerational plasticity, can influence fitness-related traits. Epigenetic marks are influenced by the genome, the environment, and their interaction, and can be inherited independently of the genome. Thus, epigenomic variation likely influences the heritability of many adaptive traits, but the extent of this influence remains largely unknown. Here we summarize the relevance of epigenetic inheritance to ecological and evolutionary processes, and review the literature on landscape-level patterns of epigenetic variation. Landscape-level patterns of epigenomic variation in plants generally show greater levels of isolation by distance and isolation by environment then is found for the genome, but the causes of these patterns are not yet clear. Linkage between the environment and epigenomic variation has been clearly shown within a single generation, but demonstrating transgenerational inheritance requires more complex breeding and/or experimental designs. Transgenerational epigenetic variation may alter the interpretation of landscape genomic studies that rely upon phenotypic analyses, but should have less influence on landscape genomic approaches that rely upon outlier analyses or genome-environment associations. We suggest that multi-generation common garden experiments conducted across multiple environments will allow researchers to understand which parts of the epigenome are inherited, as well as to parse out the relative contribution of heritable epigenetic variation to the phenotype.

  16. Epigenetic Inheritance across the Landscape.

    Science.gov (United States)

    Whipple, Amy V; Holeski, Liza M

    2016-01-01

    The study of epigenomic variation at the landscape-level in plants may add important insight to studies of adaptive variation. A major goal of landscape genomic studies is to identify genomic regions contributing to adaptive variation across the landscape. Heritable variation in epigenetic marks, resulting in transgenerational plasticity, can influence fitness-related traits. Epigenetic marks are influenced by the genome, the environment, and their interaction, and can be inherited independently of the genome. Thus, epigenomic variation likely influences the heritability of many adaptive traits, but the extent of this influence remains largely unknown. Here, we summarize the relevance of epigenetic inheritance to ecological and evolutionary processes, and review the literature on landscape-level patterns of epigenetic variation. Landscape-level patterns of epigenomic variation in plants generally show greater levels of isolation by distance and isolation by environment then is found for the genome, but the causes of these patterns are not yet clear. Linkage between the environment and epigenomic variation has been clearly shown within a single generation, but demonstrating transgenerational inheritance requires more complex breeding and/or experimental designs. Transgenerational epigenetic variation may alter the interpretation of landscape genomic studies that rely upon phenotypic analyses, but should have less influence on landscape genomic approaches that rely upon outlier analyses or genome-environment associations. We suggest that multi-generation common garden experiments conducted across multiple environments will allow researchers to understand which parts of the epigenome are inherited, as well as to parse out the relative contribution of heritable epigenetic variation to the phenotype.

  17. Daphnia as an Emerging Epigenetic Model Organism

    Directory of Open Access Journals (Sweden)

    Kami D. M. Harris

    2012-01-01

    Full Text Available Daphnia offer a variety of benefits for the study of epigenetics. Daphnia’s parthenogenetic life cycle allows the study of epigenetic effects in the absence of confounding genetic differences. Sex determination and sexual reproduction are epigenetically determined as are several other well-studied alternate phenotypes that arise in response to environmental stressors. Additionally, there is a large body of ecological literature available, recently complemented by the genome sequence of one species and transgenic technology. DNA methylation has been shown to be altered in response to toxicants and heavy metals, although investigation of other epigenetic mechanisms is only beginning. More thorough studies on DNA methylation as well as investigation of histone modifications and RNAi in sex determination and predator-induced defenses using this ecologically and evolutionarily important organism will contribute to our understanding of epigenetics.

  18. The Epigenetic Cytocrin Pathway to the Nucleus. Epigenetic Factors, Epigenetic Mediators, and Epigenetic Traits. A Biochemist Perspective

    Directory of Open Access Journals (Sweden)

    Gemma Navarro

    2017-11-01

    Full Text Available A single word, Epigenetics, underlies one exciting subject in today's Science, with different sides and with interactions with philosophy. The apparent trivial description includes everything in between genotype and phenotype that occurs for a given unique DNA sequence/genome. This Perspective article first presents an historical overview and the reasons for the lack of consensus in the field, which derives from different interpretations of the diverse operative definitions of Epigenetics. In an attempt to reconcile the different views, we propose a novel concept, the “cytocrin system.” Secondly, the article questions the inheritability requirement and makes emphasis in the epigenetic mechanisms, known or to be discovered, that provide hope for combating human diseases. Hopes in cancer are at present in deep need of deciphering mechanisms to support ad hoc therapeutic approaches. Better perspectives are for diseases of the central nervous system, in particular to combat neurodegeneration and/or cognitive deficits in Alzheimer's disease. Neurons are post-mitotic cells and, therefore, epigenetic targets to prevent neurodegeneration should operate in non-dividing diseased cells. Accordingly, epigenetic-based human therapy may not need to count much on transmissible potential.

  19. EG-09EPIGENETIC PROFILING REVEALS A CpG HYPERMETHYLATION PHENOTYPE (CIMP) ASSOCIATED WITH WORSE PROGRESSION-FREE SURVIVAL IN MENINGIOMA

    Science.gov (United States)

    Olar, Adriana; Wani, Khalida; Mansouri, Alireza; Zadeh, Gelareh; Wilson, Charmaine; DeMonte, Franco; Fuller, Gregory; Jones, David; Pfister, Stefan; von Deimling, Andreas; Sulman, Erik; Aldape, Kenneth

    2014-01-01

    BACKGROUND: Methylation profiling of solid tumors has revealed biologic subtypes, often with clinical implications. Methylation profiles of meningioma and their clinical implications are not well understood. METHODS: Ninety-two meningioma samples (n = 44 test set and n = 48 validation set) were profiled using the Illumina HumanMethylation450 BeadChip. Unsupervised clustering and analyses for recurrence-free survival (RFS) were performed. RESULTS: Unsupervised clustering of the test set using approximately 900 highly variable markers identified two clearly defined methylation subgroups. One of the groups (n = 19) showed global hypermethylation of a set of markers, analogous to CpG island methylator phenotype (CIMP). These findings were reproducible in the validation set, with 18/48 samples showing the CIMP-positive phenotype. Importantly, of 347 highly variable markers common to both the test and validation set analyses, 107 defined CIMP in the test set and 94 defined CIMP in the validation set, with an overlap of 83 markers between the two datasets. This number is much greater than expected by chance indicating reproducibly of the hypermethylated markers that define CIMP in meningioma. With respect to clinical correlation, the 37 CIMP-positive cases displayed significantly shorter RFS compared to the 55 non-CIMP cases (hazard ratio 2.9, p = 0.013). In an effort to develop a preliminary outcome predictor, a 155-marker subset correlated with RFS was identified in the test dataset. When interrogated in the validation dataset, this 155-marker subset showed a statistical trend (p < 0.1) towards distinguishing survival groups. CONCLUSIONS: This study defines the existence of a CIMP phenotype in meningioma, which involves a substantial proportion (37/92, 40%) of samples with clinical implications. Ongoing work will expand this cohort and examine identification of additional biologic differences (mutational and DNA copy number analysis) to further characterize the aberrant

  20. Epigenetic changes in solid and hematopoietic tumors.

    Science.gov (United States)

    Toyota, Minoru; Issa, Jean-Pierre J

    2005-10-01

    There are three connected molecular mechanisms of epigenetic cellular memory in mammalian cells: DNA methylation, histone modifications, and RNA interference. The first two have now been firmly linked to neoplastic transformation. Hypermethylation of CpG-rich promoters triggers local histone code modifications resulting in a cellular camouflage mechanism that sequesters gene promoters away from transcription factors and results in stable silencing. This normally restricted mechanism is ubiquitously used in cancer to silence hundreds of genes, among which some critically contribute to the neoplastic phenotype. Virtually every pathway important to cancer formation is affected by this process. Methylation profiling of human cancers reveals tissue-specific epigenetic signatures, as well as tumor-specific signatures, reflecting in particular the presence of epigenetic instability in a subset of cancers affected by the CpG island methylator phenotype. Generally, methylation patterns can be traced to a tissue-specific, proliferation-dependent accumulation of aberrant promoter methylation in aging tissues, a process that can be accelerated by chronic inflammation and less well-defined mechanisms including, possibly, diet and genetic predisposition. The epigenetic machinery can also be altered in cancer by specific lesions in epigenetic effector genes, or by aberrant recruitment of these genes by mutant transcription factors and coactivators. Epigenetic patterns are proving clinically useful in human oncology via risk assessment, early detection, and prognostic classification. Pharmacologic manipulation of these patterns-epigenetic therapy-is also poised to change the way we treat cancer in the clinic.

  1. Isolation of monoclonal antibodies with predetermined conformational epitope specificity.

    Directory of Open Access Journals (Sweden)

    Anton M Sholukh

    Full Text Available Existing technologies allow isolating antigen-specific monoclonal antibodies (mAbs from B cells. We devised a direct approach to isolate mAbs with predetermined conformational epitope specificity, using epitope mimetics (mimotopes that reflect the three-dimensional structure of given antigen subdomains. We performed differential biopanning using bacteriophages encoding random peptide libraries and polyclonal antibodies (Abs that had been affinity-purified with either native or denatured antigen. This strategy yielded conformational mimotopes. We then generated mimotope-fluorescent protein fusions, which were used as baits to isolate single memory B cells from rhesus monkeys (RMs. To amplify RM immunoglobulin variable regions, we developed RM-specific PCR primers and generated chimeric simian-human mAbs with predicted epitope specificity. We established proof-of-concept of our strategy by isolating mAbs targeting the conformational V3 loop crown of HIV Env; the new mAbs cross-neutralized viruses of different clades. The novel technology allows isolating mAbs from RMs or other hosts given experimental immunogens or infectious agents.

  2. Process for preparing schottky diode contacts with predetermined barrier heights

    Science.gov (United States)

    Chang, Y. Austin; Jan, Chia-Hong; Chen, Chia-Ping

    1996-01-01

    A process is provided for producing a Schottky diode having a preselected barrier height .phi..sub.Bn. The substrate is preferably n-GaAs, the metallic contact is derived from a starting alloy of the Formula [.SIGMA.M.sub..delta. ](Al.sub.x Ga.sub.1-x) wherein: .SIGMA.M is a moiety which consists of at least one M, and when more than one M is present, each M is different, M is a Group VIII metal selected from the group consisting of nickel, cobalt, ruthenium, rhodium, indium and platinum, .delta. is a stoichiometric coefficient whose total value in any given .SIGMA.M moiety is 1, and x is a positive number between 0 and 1 (that is, x ranges from greater than 0 to less than 1). Also, the starting alloy is capable of forming with the substrate a two phase equilibrium reciprocal system of the binary alloy mixture [.SIGMA.M.sub..delta. ]Ga-[.SIGMA.M.sub..delta. ]Al-AlAs-GaAs. When members of an alloy subclass within this Formula are each preliminarily correlated with the barrier height .phi..sub.Bn of a contact producable therewith, then Schottky diodes of predetermined barrier heights are producable by sputtering and annealing. Further provided are the product Schottky diodes that are produced according to this process.

  3. Epigenetics of obesity: beyond the genome sequence.

    Science.gov (United States)

    Cordero, Paul; Li, Jiawei; Oben, Jude A

    2015-07-01

    After the study of the gene code as a trigger for obesity, epigenetic code has appeared as a novel tool in the diagnosis, prognosis and treatment of obesity, and its related comorbidities. This review summarizes the status of the epigenetic field associated with obesity, and the current epigenetic-based approaches for obesity treatment. Thanks to technical advances, novel and key obesity-associated polymorphisms have been described by genome-wide association studies, but there are limitations with their predictive power. Epigenetics is also studied for disease association, which involves decoding of the genome information, transcriptional status and later phenotypes. Obesity could be induced during adult life by feeding and other environmental factors, and there is a strong association between obesity features and specific epigenetic patterns. These patterns could be established during early life stages, and programme the risk of obesity and its comorbidities during adult life. Furthermore, recent studies have shown that DNA methylation profile could be applied as biomarkers of diet-induced weight loss treatment. High-throughput technologies, recently implemented for commercial genetic test panels, could soon lead to the creation of epigenetic test panels for obesity. Nonetheless, epigenetics is a modifiable risk factor, and different dietary patterns or environmental insights during distinct stages of life could lead to rewriting of the epigenetic profile.

  4. The Emerging Role of Epigenetics in Inflammation and Immunometabolism.

    Science.gov (United States)

    Raghuraman, Sukanya; Donkin, Ida; Versteyhe, Soetkin; Barrès, Romain; Simar, David

    2016-11-01

    Recent research developments have shed light on the risk factors contributing to metabolic complications, implicating both genetic and environmental factors, potentially integrated by epigenetic mechanisms. Distinct epigenetic changes in immune cells are frequently observed in obesity and type 2 diabetes mellitus, and these are associated with alterations in the phenotype, function, and trafficking patterns of these cells. The first step in the development of effective therapeutic strategies is the identification of distinct epigenetic signatures associated with metabolic disorders. In this review we provide an overview of the epigenetic mechanisms influencing immune cell phenotype and function, summarize current knowledge about epigenetic changes affecting immune functions in the context of metabolic diseases, and discuss the therapeutic options currently available to counteract epigenetically driven metabolic complications. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. [Epigenetics of schizophrenia: a review].

    Science.gov (United States)

    Rivollier, F; Lotersztajn, L; Chaumette, B; Krebs, M-O; Kebir, O

    2014-10-01

    Schizophrenia is a frequent and disabling disease associated with heterogeneous psychiatric phenotypes. It emerges during childhood, adolescence or young adulthood and has dramatic consequences for the affected individuals, causing considerable familial and social burden, as well as increasing health expenses. Although some progress has been made in the understanding of their physiopathology, many questions remain unsolved, and the disease is still poorly understood. The prevailing hypothesis regarding psychotic disorders proposes that a combination of genetic and/or environmental factors, during critical periods of brain development increases the risk for these illnesses. Epigenetic regulations, such as DNA methylation, can mediate gene x environment interactions at the level of the genome and may provide a potential substrate to explain the variability in symptom severity and family heritability. Initially, epigenetics was used to design mitotic and meiotic changes in gene transcription that could not be attributed to genetic mutations. It referred later to changes in the epigenome not transmitted through the germline. Thus, epigenetics refers to a wide range of molecular mechanisms including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. These mechanisms alter the way the transcriptional factors bind the DNA, modulating its expression. Prenatal and postnatal environmental factors may affect these epigenetics factors, having responsability in long-term DNA transcription, and influencing the development of psychiatric disorders. The object of this review is to present the state of knowledge in epigenetics of schizophrenia, outlining the most recent findings in the matter. We did so using Pubmed, researching words such as 'epigenetics', 'epigenetic', 'schizophrenia', 'psychosis', 'psychiatric'. This review summarizes evidences mostly for two epigenetic mechanisms: DNA methylation and post

  6. Assessing the Impact of Transgenerational Epigenetic Variation on Complex Traits

    NARCIS (Netherlands)

    Johannes, Frank; Porcher, Emmanuelle; Teixeira, Felipe K.; Saliba-Colombani, Vera; Simon, Matthieu; Agier, Nicolas; Bulski, Agnes; Albuisson, Juliette; Heredia, Fabiana; Audigier, Pascal; Bouchez, David; Dillmann, Christine; Guerche, Philippe; Hospital, Frederic; Colot, Vincent

    Loss or gain of DNA methylation can affect gene expression and is sometimes transmitted across generations. Such epigenetic alterations are thus a possible source of heritable phenotypic variation in the absence of DNA sequence change. However, attempts to assess the prevalence of stable epigenetic

  7. Epigenetics of human asthma and allergy: promises to keep.

    Science.gov (United States)

    Devries, Avery; Vercelli, Donata

    2013-09-01

    The interest in asthma epigenetics is high because epigenetic mechanisms likely contribute to the environmental origins of the disease and its phenotypic variability. This review presents the main findings of asthma epigenetics and the challenges that still delay progress. We examined the current literature on asthma epigenetics (31 reviews and 25 original data publications). We focused on DNA methylation studies in populations. Both genome-wide and candidate gene studies have explored DNA methylation in allergic disease. Genome-wide studies ask whether and which regions of the genome are differentially methylated in relation to the phenotype of interest. Identification of such regions provides clues about the identity of the genes, pathways and networks underpinning a phenotype and connects these networks to the phenotype through epigenetic mechanisms. Candidate gene studies examine DNA methylation in genes chosen because of their known or hypothesized role in immunity, responses to environmental stimuli or disease pathogenesis. Most existing studies in asthma and allergy focused on candidate genes involved in the response to environmental pollutants. Asthma epigenetics is still in its infancy. The paucity of primary literature originates from methodological and analytical challenges of genome-wide studies, the difficulties in interpreting small differences in DNA methylation, and the need to develop robust bioinformatic tools for pathway, network and system analyses of epigenetic data. Once these challenges have been overcome, epigenetic studies will likely provide important insights about the inception and pathogenesis of allergic disease and will help define disease endotypes.

  8. Epigenetic variation contributes to environmental adaptation of Arabidopsis thaliana

    NARCIS (Netherlands)

    Kooke, R.; Keurentjes, J.J.B.

    2015-01-01

    Epigenetic variation is frequently observed in plants and direct relationships between differences in DNA methylation and phenotypic responses to changing environments have often been described. The identification of contributing genetic loci, however, was until recently hampered by the lack of

  9. Epigenetics and Bruxism: Possible Role of Epigenetics in the Etiology of Bruxism.

    Science.gov (United States)

    Čalić, Aleksandra; Peterlin, Borut

    2015-01-01

    Bruxism is defined as a repetitive jaw muscle activity characterized by clenching or grinding of the teeth and/or bracing or thrusting of the mandible. There are two distinct circadian phenotypes for bruxism: sleep bruxism (SB) and awake bruxism, which are considered separate entities due to the putative difference in their etiology and phenotypic variance. The detailed etiology of bruxism so far remains unknown. Recent theories suggest the central regulation of certain pathophysiological or psychological pathways. Current proposed causes of bruxism appear to be a combination of genetic and environmental (G×E) factors, with epigenetics providing a robust framework for investigating G×E interactions, and their involvement in bruxism makes it a suitable candidate for epigenetic research. Both types of bruxism are associated with certain epigenetically determined disorders, such as Rett syndrome (RTT), Prader-Willi syndrome (PWS), and Angelman syndrome (AS), and these associations suggest a mechanistic link between epigenetic deregulation and bruxism. The present article reviews the possible role of epigenetic mechanisms in the etiology of both types of bruxism based on the epigenetic pathways involved in the pathophysiology of RTT, PWS, and AS, and on other epigenetic disruptions associated with risk factors for bruxism, including sleep disorders, altered stress response, and psychopathology.

  10. Prostate cancer epigenetics and its clinical implications.

    Science.gov (United States)

    Yegnasubramanian, Srinivasan

    2016-01-01

    Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.

  11. Prostate cancer epigenetics and its clinical implications

    Directory of Open Access Journals (Sweden)

    Srinivasan Yegnasubramanian

    2016-01-01

    Full Text Available Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.

  12. Epigenetics: relevance and implications for public health.

    Science.gov (United States)

    Rozek, Laura S; Dolinoy, Dana C; Sartor, Maureen A; Omenn, Gilbert S

    2014-01-01

    Improved understanding of the multilayer regulation of the human genome has led to a greater appreciation of environmental, nutritional, and epigenetic risk factors for human disease. Chromatin remodeling, histone tail modifications, and DNA methylation are dynamic epigenetic changes responsive to external stimuli. Careful interpretation can provide insights for actionable public health through collaboration between population and basic scientists and through integration of multiple data sources. We review key findings in environmental epigenetics both in human population studies and in animal models, and discuss the implications of these results for risk assessment and public health protection. To ultimately succeed in identifying epigenetic mechanisms leading to complex phenotypes and disease, researchers must integrate the various animal models, human clinical approaches, and human population approaches while paying attention to life-stage sensitivity, to generate effective prescriptions for human health evaluation and disease prevention.

  13. MSAP In Tiger Snakes: Island Populations Are Epigenetically More Divergent

    OpenAIRE

    Konate, Moumouni; Lopez, Carlos; Thomson, Vicki

    2017-01-01

    Research on changes in phenotypic plasticity within wild animal populations is centuries old, however far fewer studies have investigated the role that epigenetics play in the development or persistence of natural variation in response to environmental change. Tiger snakes (Notechis scutatus) are an ideal study organism to investigate the link between epigenetics and phenotypic responses to environmental change, as they live on a range of offshore islands with different environments and prey ...

  14. Understanding Neurological Disease Mechanisms in the Era of Epigenetics

    Science.gov (United States)

    Qureshi, Irfan A.; Mehler, Mark F.

    2015-01-01

    The burgeoning field of epigenetics is making a significant impact on our understanding of brain evolution, development, and function. In fact, it is now clear that epigenetic mechanisms promote seminal neurobiological processes, ranging from neural stem cell maintenance and differentiation to learning and memory. At the molecular level, epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues, including the deployment of cell type–specific gene networks and those underlying synaptic plasticity. Pharmacological and genetic manipulation of epigenetic factors can, in turn, induce remarkable changes in neural cell identity and cognitive and behavioral phenotypes. Not surprisingly, it is also becoming apparent that epigenetics is intimately involved in neurological disease pathogenesis. Herein, we highlight emerging paradigms for linking epigenetic machinery and processes with neurological disease states, including how (1) mutations in genes encoding epigenetic factors cause disease, (2) genetic variation in genes encoding epigenetic factors modify disease risk, (3) abnormalities in epigenetic factor expression, localization, or function are involved in disease pathophysiology, (4) epigenetic mechanisms regulate disease-associated genomic loci, gene products, and cellular pathways, and (5) differential epigenetic profiles are present in patient-derived central and peripheral tissues. PMID:23571666

  15. Rice epigenomics and epigenetics: challenges and opportunities.

    Science.gov (United States)

    Chen, Xiangsong; Zhou, Dao-Xiu

    2013-05-01

    During recent years rice genome-wide epigenomic information such as DNA methylation and histone modifications, which are important for genome activity has been accumulated. The function of a number of rice epigenetic regulators has been studied, many of which are found to be involved in a diverse range of developmental and stress-responsive pathways. Analysis of epigenetic variations among different rice varieties indicates that epigenetic modification may lead to inheritable phenotypic variation. Characterizing phenotypic consequences of rice epigenomic variations and the underlining chromatin mechanism and identifying epialleles related to important agronomic traits may provide novel strategies to enhance agronomically favorable traits and grain productivity in rice. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Environmental Epigenetics: Crossroad between Public Health, Lifestyle, and Cancer Prevention

    Science.gov (United States)

    Romani, Massimo; Pistillo, Maria Pia; Banelli, Barbara

    2015-01-01

    Epigenetics provides the key to transform the genetic information into phenotype and because of its reversibility it is considered an ideal target for therapeutic interventions. This paper reviews the basic mechanisms of epigenetic control: DNA methylation, histone modifications, chromatin remodeling, and ncRNA expression and their role in disease development. We describe also the influence of the environment, lifestyle, nutritional habits, and the psychological influence on epigenetic marks and how these factors are related to cancer and other diseases development. Finally we discuss the potential use of natural epigenetic modifiers in the chemoprevention of cancer to link together public health, environment, and lifestyle. PMID:26339624

  17. Environment, epigenetics and reproduction.

    Science.gov (United States)

    Skinner, Michael K

    2017-07-01

    A conference summary of the third biannual Kenya Africa Conference "Environment, Epigenetics and Reproduction" is provided. A partial special Environmental Epigenetics issue containing a number of papers in Volume 3, Issue 3 and 4 are discussed.

  18. Epigenetic mechanisms in the initiation of hematological malignancies

    Directory of Open Access Journals (Sweden)

    Ali Maleki

    2011-10-01

    Full Text Available Background: Cancer development is not restricted to the genetic changes, but also to epigenetic changes. Epigenetic processes are very important in the development of hematological malignancies. The main epigenetic alterations are aberrations in DNA methylation, post-translational modifications of histones, chromatin remodeling and microRNAs patterns, and these are associated with tumor genesis. All the various cellular pathways contributing to the neoplastic phenotype are affected by epigenetic genes in cancer. These pathways can be explored as biomarkers in clinical use for early detection of disease, malignancy classification and response to treatment with classical chemotherapy agents and epigenetic drugs. Materials and Method: A literature review was performed using PUBMED from 1985 to 2008. Cross referencing of discovered articles was also reviewed.Results: In chronic lymphocytic leukemia, regional hypermethylation of gene promoters leads to gene silencing. Many of these genes have tumor suppressor phenotypes. In myelodysplastic syndrome (MDS, CDKN2B (alias, P15, a cyclin-dependent kinase inhibitor that negatively regulates the cell cycle, has been shown to be hypermethylated in marrow stem (CD34+ cells in patients with MDS. At present both Vidaza and Decitabine (DNA methyltransferase inhibitors are approved for the treatment of MDS.Conclusion: Unlike mutations or deletions, DNA hypermethylation and histone deacetylation are potentially reversible by pharmacological inhibition, therefore those epigenetic changes have been recognized as promising novel therapeutic targets in hematopoietic malignances. In this review, we discussed molecular mechanisms of epigenetics, epigenetic changes in hematological malignancies and epigenetic based treatments

  19. Landscaping plant epigenetics.

    Science.gov (United States)

    McKeown, Peter C; Spillane, Charles

    2014-01-01

    The understanding of epigenetic mechanisms is necessary for assessing the potential impacts of epigenetics on plant growth, development and reproduction, and ultimately for the response of these factors to evolutionary pressures and crop breeding programs. This volume highlights the latest in laboratory and bioinformatic techniques used for the investigation of epigenetic phenomena in plants. Such techniques now allow genome-wide analyses of epigenetic regulation and help to advance our understanding of how epigenetic regulatory mechanisms affect cellular and genome function. To set the scene, we begin with a short background of how the field of epigenetics has evolved, with a particular focus on plant epigenetics. We consider what has historically been understood by the term "epigenetics" before turning to the advances in biochemistry, molecular biology, and genetics which have led to current-day definitions of the term. Following this, we pay attention to key discoveries in the field of epigenetics that have emerged from the study of unusual and enigmatic phenomena in plants. Many of these phenomena have involved cases of non-Mendelian inheritance and have often been dismissed as mere curiosities prior to the elucidation of their molecular mechanisms. In the penultimate section, consideration is given to how advances in molecular techniques are opening the doors to a more comprehensive understanding of epigenetic phenomena in plants. We conclude by assessing some opportunities, challenges, and techniques for epigenetic research in both model and non-model plants, in particular for advancing understanding of the regulation of genome function by epigenetic mechanisms.

  20. The role of non-genetic inheritance in evolutionary rescue: epigenetic buffering, heritable bet hedging and epigenetic traps.

    Science.gov (United States)

    O'Dea, Rose E; Noble, Daniel W A; Johnson, Sheri L; Hesselson, Daniel; Nakagawa, Shinichi

    2016-01-01

    Rapid environmental change is predicted to compromise population survival, and the resulting strong selective pressure can erode genetic variation, making evolutionary rescue unlikely. Non-genetic inheritance may provide a solution to this problem and help explain the current lack of fit between purely genetic evolutionary models and empirical data. We hypothesize that epigenetic modifications can facilitate evolutionary rescue through 'epigenetic buffering'. By facilitating the inheritance of novel phenotypic variants that are generated by environmental change-a strategy we call 'heritable bet hedging'-epigenetic modifications could maintain and increase the evolutionary potential of a population. This process may facilitate genetic adaptation by preserving existing genetic variation, releasing cryptic genetic variation and/or facilitating mutations in functional loci. Although we show that examples of non-genetic inheritance are often maladaptive in the short term, accounting for phenotypic variance and non-adaptive plasticity may reveal important evolutionary implications over longer time scales. We also discuss the possibility that maladaptive epigenetic responses may be due to 'epigenetic traps', whereby evolutionarily novel factors (e.g. endocrine disruptors) hack into the existing epigenetic machinery. We stress that more ecologically relevant work on transgenerational epigenetic inheritance is required. Researchers conducting studies on transgenerational environmental effects should report measures of phenotypic variance, so that the possibility of both bet hedging and heritable bet hedging can be assessed. Future empirical and theoretical work is required to assess the relative importance of genetic and epigenetic variation, and their interaction, for evolutionary rescue.

  1. Epigenetic Therapy in Human Choriocarcinoma

    Directory of Open Access Journals (Sweden)

    Hisashi Narahara

    2010-09-01

    Full Text Available Because epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in choriocarcinomas, novel compounds endowed with a histone deacetylase (HDAC inhibitory activity are an attractive therapeutic approach. HDAC inhibitors (HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and the expression of genes related to the malignant phenotype in choriocarcinoma cell lines. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating choriocarcinoma, with a special focus on preclinical studies.

  2. Epigenetic regulation of hematopoietic stem cell aging

    International Nuclear Information System (INIS)

    Beerman, Isabel; Rossi, Derrick J.

    2014-01-01

    Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging

  3. Transgenerational epigenetic effects on animal behaviour.

    Science.gov (United States)

    Jensen, Per

    2013-12-01

    Over the last decade a shift in paradigm has occurred with respect to the interaction between environment and genes. It is now clear that animal genomes are regulated to a large extent as a result of input from environmental events and experiences, which cause short- and long-term modifications in epigenetic markings of DNA and histones. In this review, the evidence that such epigenetic modifications can affect the behaviour of animals is explored, and whether such acquired behaviour alterations can transfer across generation borders. First, the mechanisms by which experiences cause epigenetic modifications are examined. This includes, for example, methylation of cytosine in CpG positions and acetylation of histones, and studies showing that this can be modified by early experiences. Secondly, the evidence that specific modifications in the epigenome can be the cause of behaviour variation is reviewed. Thirdly, the extent to which this phenotypically active epigenetic variants can be inherited either through the germline or through reoccurring environmental conditions is examined. A particularly interesting observation is that epigenetic modifications are often linked to stress, and may possibly be mediated by steroid effects. Finally, the idea that transgenerationally stable epigenetic variants may serve as substrates for natural selection is explored, and it is speculated that they may even predispose for directed, non-random mutations. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Epigenetic regulation of hematopoietic stem cell aging

    Energy Technology Data Exchange (ETDEWEB)

    Beerman, Isabel, E-mail: isabel.beerman@childrens.harvard.edu [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States); Rossi, Derrick J. [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States)

    2014-12-10

    Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.

  5. One gene, many phenotypes | Shawky | Egyptian Journal of Medical ...

    African Journals Online (AJOL)

    ... mechanisms underlying genotype-phenotype discrepancies is important, as it will move clinical genetics towards predictive medicine, allowing better selection of therapeutic strategies and individualized counseling of persons affected with genetic disorders. Keywords: Gene, phenotype, mosaicism, epigenetics, pleiotropy ...

  6. Epigenetics and Epigenomics of Plants.

    Science.gov (United States)

    Yadav, Chandra Bhan; Pandey, Garima; Muthamilarasan, Mehanathan; Prasad, Manoj

    2018-01-23

    The genetic material DNA in association with histone proteins forms the complex structure called chromatin, which is prone to undergo modification through certain epigenetic mechanisms including cytosine DNA methylation, histone modifications, and small RNA-mediated methylation. Alterations in chromatin structure lead to inaccessibility of genomic DNA to various regulatory proteins such as transcription factors, which eventually modulates gene expression. Advancements in high-throughput sequencing technologies have provided the opportunity to study the epigenetic mechanisms at genome-wide levels. Epigenomic studies using high-throughput technologies will widen the understanding of mechanisms as well as functions of regulatory pathways in plant genomes, which will further help in manipulating these pathways using genetic and biochemical approaches. This technology could be a potential research tool for displaying the systematic associations of genetic and epigenetic variations, especially in terms of cytosine methylation onto the genomic region in a specific cell or tissue. A comprehensive study of plant populations to correlate genotype to epigenotype and to phenotype, and also the study of methyl quantitative trait loci (QTL) or epiGWAS, is possible by using high-throughput sequencing methods, which will further accelerate molecular breeding programs for crop improvement. Graphical Abstract.

  7. Epigenetics in comparative biology: why we should pay attention.

    Science.gov (United States)

    Burggren, Warren W; Crews, David

    2014-07-01

    The past decade has seen an explosion of articles in scientific journals involving non-genetic influences on phenotype through modulation of gene function without changes in gene sequence. The excitement in modern molecular biology surrounding the impact exerted by the environment on development of the phenotype is focused largely on mechanism and has not incorporated questions asked (and answers provided) by early philosophers, biologists, and psychologists. As such, this emergence of epigenetic studies is somewhat "old wine in new bottles" and represents a reformulation of the old debate of preformationism versus epigenesis-one resolved in the 1800s. Indeed, this tendency to always look forward, with minimal concern or regard of what has gone before, has led to the present situation in which "true" epigenetic studies are believed to consist of one of two schools. The first is primarily medically based and views epigenetic mechanisms as pathways for disease (e.g., "the epigenetics of cancer"). The second is primarily from the basic sciences, particularly molecular genetics, and regards epigenetics as a potentially important mechanism for organisms exposed to variable environments across multiple generations. There is, however, a third, and separate, school based on the historical literature and debates and regards epigenetics as more of a perspective than a phenomenon. Against this backdrop, comparative integrative biologists are particularly well-suited to understand epigenetic phenomena as a way for organisms to respond rapidly with modified phenotypes (relative to natural selection) to changes in the environment. Using evolutionary principles, it is also possible to interpret "sunsetting" of modified phenotypes when environmental conditions result in a disappearance of the epigenetic modification of gene regulation. Comparative integrative biologists also recognize epigenetics as a potentially confounding source of variation in their data. Epigenetic

  8. Method of producing a diesel fuel blend having a pre-determined flash-point and pre-determined increase in cetane number

    Science.gov (United States)

    Waller, Francis Joseph; Quinn, Robert

    2004-07-06

    The present invention relates to a method of producing a diesel fuel blend having a pre-determined flash-point and a pre-determined increase in cetane number over the stock diesel fuel. Upon establishing the desired flash-point and increase in cetane number, an amount of a first oxygenate with a flash-point less than the flash-point of the stock diesel fuel and a cetane number equal to or greater than the cetane number of the stock diesel fuel is added to the stock diesel fuel in an amount sufficient to achieve the pre-determined increase in cetane number. Thereafter, an amount of a second oxygenate with a flash-point equal to or greater than the flash-point of the stock diesel fuel and a cetane number greater than the cetane number of the stock diesel fuel is added to the stock diesel fuel in an amount sufficient to achieve the pre-determined increase in cetane number.

  9. Nature, Nurture and Epigenetics

    Science.gov (United States)

    Crews, David; Gillette, Ross; Miller-Crews, Isaac; Gore, Andrea C.; Skinner, Michael K.

    2015-01-01

    Real life by definition combines heritability (e.g., the legacy of exposures) and experience (e.g. stress during sensitive or ‘critical’ periods), but how to study or even model this interaction has proven difficult. The hoary concept of evaluating traits according to nature vs. nurture continues to persist despite repeated demonstrations that it retards, rather than advances, our understanding of biological processes. Behavioral genetics has proven the obvious, that genes influences behavior and, vice versa, that behavior influences genes. The concept of Genes X Environment (G X E) and its modern variants was viewed as an improvement on nature-nurture but has proven that, except in rare instances, it is not possible to fractionate phenotypes into these constituent elements. The entanglement inherent in terms such as nature-nurture or GXE is a Gordian knot that cannot be dissected or even split. Given that the world today is not what it was less than a century ago, yet the arbitrator (differential survival and reproduction) has stayed constant, de novo principles and practices are needed to better predict what the future holds. Put simply, the transformation that is now occurring within and between individuals as a product of global endocrine disruption is quite independent of what has been regarded as evolution by selection. This new perspective should focus on how epigenetic modifications might revise approaches to understand how the phenotype and, in particular its components, is shaped. In this review we summarize the literature in this developing area, focusing on our research on the fungicide vinclozolin. PMID:25102229

  10. Nature, nurture and epigenetics.

    Science.gov (United States)

    Crews, David; Gillette, Ross; Miller-Crews, Isaac; Gore, Andrea C; Skinner, Michael K

    2014-12-01

    Real life by definition combines heritability (e.g., the legacy of exposures) and experience (e.g. stress during sensitive or 'critical' periods), but how to study or even model this interaction has proven difficult. The hoary concept of evaluating traits according to nature versus nurture continues to persist despite repeated demonstrations that it retards, rather than advances, our understanding of biological processes. Behavioral genetics has proven the obvious, that genes influence behavior and, vice versa, that behavior influences genes. The concept of Genes X Environment (G X E) and its modern variants was viewed as an improvement on nature-nurture but has proven that, except in rare instances, it is not possible to fractionate phenotypes into these constituent elements. The entanglement inherent in terms such as nature-nurture or G X E is a Gordian knot that cannot be dissected or even split. Given that the world today is not what it was less than a century ago, yet the arbitrator (differential survival and reproduction) has stayed constant, de novo principles and practices are needed to better predict what the future holds. Put simply, the transformation that is now occurring within and between individuals as a product of global endocrine disruption is quite independent of what has been regarded as evolution by selection. This new perspective should focus on how epigenetic modifications might revise approaches to understand how the phenotype and, in particular its components, is shaped. In this review we summarize the literature in this developing area, focusing on our research on the fungicide vinclozolin. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Transgenerational effects of stress exposure on offspring phenotypes in apomictic dandelion

    NARCIS (Netherlands)

    Verhoeven, K.J.F.; Van Gurp, T.P.

    2012-01-01

    Heritable epigenetic modulation of gene expression is a candidate mechanism to explain parental environmental effects on offspring phenotypes, but current evidence for environment-induced epigenetic changes that persist in offspring generations is scarce. In apomictic dandelions, exposure to various

  12. Transgenerational Effects of Stress Exposure on Offspring Phenotypes in Apomictic Dandelion

    NARCIS (Netherlands)

    Verhoeven, K.J.F.; Gurp, van T.P.

    2012-01-01

    Heritable epigenetic modulation of gene expression is a candidate mechanism to explain parental environmental effects on offspring phenotypes, but current evidence for environment-induced epigenetic changes that persist in offspring generations is scarce. In apomictic dandelions, exposure to various

  13. Epigenetics Research on the International Space Station

    Science.gov (United States)

    Love, John; Cooley, Vic

    2016-01-01

    The International Space Station (ISS) is a state-of-the orbiting laboratory focused on advancing science and technology research. Experiments being conducted on the ISS include investigations in the emerging field of Epigenetics. Epigenetics refers to stably heritable changes in gene expression or cellular phenotype (the transcriptional potential of a cell) resulting from changes in a chromosome without alterations to the underlying DNA nucleotide sequence (the genetic code), which are caused by external or environmental factors, such as spaceflight microgravity. Molecular mechanisms associated with epigenetic alterations regulating gene expression patterns include covalent chemical modifications of DNA (e.g., methylation) or histone proteins (e.g., acetylation, phorphorylation, or ubiquitination). For example, Epigenetics ("Epigenetics in Spaceflown C. elegans") is a recent JAXA investigation examining whether adaptations to microgravity transmit from one cell generation to another without changing the basic DNA of the organism. Mouse Epigenetics ("Transcriptome Analysis and Germ-Cell Development Analysis of Mice in Space") investigates molecular alterations in organ-specific gene expression patterns and epigenetic modifications, and analyzes murine germ cell development during long term spaceflight, as well as assessing changes in offspring DNA. NASA's first foray into human Omics research, the Twins Study ("Differential effects of homozygous twin astronauts associated with differences in exposure to spaceflight factors"), includes investigations evaluating differential epigenetic effects via comprehensive whole genome analysis, the landscape of DNA and RNA methylation, and biomolecular changes by means of longitudinal integrated multi-omics research. And the inaugural Genes in Space student challenge experiment (Genes in Space-1) is aimed at understanding how epigenetics plays a role in immune system dysregulation by assaying DNA methylation in immune cells

  14. Epigenetics and Cellular Metabolism

    Directory of Open Access Journals (Sweden)

    Wenyi Xu

    2016-01-01

    Full Text Available Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc. is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well.

  15. Epigenetics and obesity

    OpenAIRE

    Stöger, Reinhard

    2008-01-01

    Common DNA sequence variants inadequately explain variability in fat mass among individuals. Abnormal body weights are characteristic of specific imprinted-gene disorders. However, the relevance of imprinted genes to our understanding of obesity among the general population is uncertain. Hitherto unidentified imprinted genes and epigenetic mosaicism are two of the challenges for this emerging field of epigenetics. Subtle epigenetic differences in imprinted genes and gene networks are likely t...

  16. Epigenetics: beyond genes

    CSIR Research Space (South Africa)

    Fossey, A

    2009-06-01

    Full Text Available in forestry breeding. Keywords Gene regulation; chromatin; histone code hyporthesis; RNA silencing; post transcriptional gene silencing; forestry. Introduction to epigenetic phenomena Most living organisms share a vast amount of genetic information... (Rapp and Wendel, 2005). Epigenetic phenomena pervade all aspects of cell proliferation and plant development and are often in conflict with Mendelian models of genetics (Grant-Downton and Dickinson, 2005). A key element in many epigenetic effects...

  17. Epigenetic Regulation of Adipokines

    Directory of Open Access Journals (Sweden)

    Tho X. Pham

    2017-08-01

    Full Text Available Adipose tissue expansion in obesity leads to changes in the expression of adipokines, adipocyte-specific hormones that can regulate whole body energy metabolism. Epigenetic regulation of gene expression is a mechanism by which cells can alter gene expression through the modifications of DNA and histones. Epigenetic mechanisms, such as DNA methylation and histone modifications, are intimately tied to energy metabolism due to their dependence on metabolic intermediates such as S-adenosylmethionine and acetyl-CoA. Altered expression of adipokines in obesity may be due to epigenetic changes. The goal of this review is to highlight current knowledge of epigenetic regulation of adipokines.

  18. Twins for epigenetic studies of human aging and development

    DEFF Research Database (Denmark)

    Tan, Qihua; Christiansen, Lene; Thomassen, Mads

    2013-01-01

    Most of the complex traits including aging phenotypes are caused by the interaction between genome and environmental conditions and the interface of epigenetics may be a central mechanism. Although modern technologies allow us high-throughput profiling of epigenetic patterns already at genome level...... and environmental contributions to human diseases and complex traits. In the era of functional genomics, the valuable sample of twins is helping to bridge the gap between gene activity and the environments through epigenetic mechanisms unlimited by DNA sequence variations. We propose to extend the classical twin...... design to study the aging-related molecular epigenetic phenotypes and link them with environmental exposures especially early life events. Different study designs and application issues will be highlighted and novel approaches introduced with aim at making uses of twins in assessing the environmental...

  19. Mitochondrial regulation of epigenetics and its role in human diseases

    DEFF Research Database (Denmark)

    Minocherhomji, Sheroy; Tollefsbol, Trygve O; Singh, Keshav K

    2012-01-01

    as the sole pathogenic factor suggesting that additional mechanisms contribute to lack of genotype and clinical phenotype correlationship. An increasing number of studies have identified a possible effect on the epigenetic landscape of the nuclear genome as a consequence of mitochondrial dysfunction....... In particular, these studies demonstrate reversible or irreversible changes in genomic DNA methylation profiles of the nuclear genome. Here we review how mitochondria damage checkpoint (mitocheckpoint) induces epigenetic changes in the nucleus. Persistent pathogenic mutations in mtDNA may also lead...... to epigenetic changes causing genomic instability in the nuclear genome. We propose that "mitocheckpoint" mediated epigenetic and genetic changes may play key roles in phenotypic variation related to mitochondrial diseases or host of human diseases in which mitochondrial defect plays a primary role....

  20. Multiple levels of epigenetic control for bone biology and pathology.

    Science.gov (United States)

    Montecino, Martin; Stein, Gary; Stein, Janet; Zaidi, Kaleem; Aguilar, Rodrigo

    2015-12-01

    Multiple dimensions of epigenetic control contribute to regulation of gene expression that governs bone biology and pathology. Once confined to DNA methylation and a limited number of post-translational modifications of histone proteins, the definition of epigenetic mechanisms is expanding to include contributions of non-coding RNAs and mitotic bookmarking, a mechanism for retaining phenotype identity during cell proliferation. Together these different levels of epigenetic control of physiological processes and their perturbations that are associated with compromised gene expression during the onset and progression of disease, have contributed to an unprecedented understanding of the activities (operation) of the genomic landscape. Here, we address general concepts that explain the contribution of epigenetic control to the dynamic regulation of gene expression during eukaryotic transcription. This article is part of a Special Issue entitled Epigenetics and Bone. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Epigenetic regulation of vascular smooth muscle cell function in atherosclerosis.

    Science.gov (United States)

    Findeisen, Hannes M; Kahles, Florian K; Bruemmer, Dennis

    2013-04-01

    Epigenetics involve heritable and acquired changes in gene transcription that occur independently of the DNA sequence. Epigenetic mechanisms constitute a hierarchic upper-level of transcriptional control through complex modifications of chromosomal components and nuclear structures. These modifications include, for example, DNA methylation or post-translational modifications of core histones; they are mediated by various chromatin-modifying enzymes; and ultimately they define the accessibility of a transcriptional complex to its target DNA. Integrating epigenetic mechanisms into the pathophysiologic concept of complex and multifactorial diseases such as atherosclerosis may significantly enhance our understanding of related mechanisms and provide promising therapeutic approaches. Although still in its infancy, intriguing scientific progress has begun to elucidate the role of epigenetic mechanisms in vascular biology, particularly in the control of smooth muscle cell phenotypes. In this review, we will summarize epigenetic pathways in smooth muscle cells, focusing on mechanisms involved in the regulation of vascular remodeling.

  2. Epigenetics and maternal nutrition: nature v. nurture.

    Science.gov (United States)

    Simmons, Rebecca

    2011-02-01

    Under- and over-nutrition during pregnancy has been linked to the later development of diseases such as diabetes and obesity. Epigenetic modifications may be one mechanism by which exposure to an altered intrauterine milieu or metabolic perturbation may influence the phenotype of the organism much later in life. Epigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene expression from one generation of cells to the next. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodelling and histone modifications play key roles in adipogenesis and the development of obesity. Epigenetic modifications affecting processes important to glucose regulation and insulin secretion have been described in the pancreatic β-cells and muscle of the intrauterine growth-retarded offspring, characteristics essential to the pathophysiology of type-2 diabetes. Epigenetic regulation of gene expression contributes to both adipocyte determination and differentiation in in vitro models. The contributions of histone acetylation, histone methylation and DNA methylation to the process of adipogenesis in vivo remain to be evaluated.

  3. Obesity: epigenetic aspects.

    Science.gov (United States)

    Kaushik, Prashant; Anderson, James T

    2016-06-01

    Epigenetics, defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base pair sequence has been shown to play an important role in the etiopathogenesis of obesity. Obesity is associated with extensive gene expression changes in tissues throughout the body. Epigenetics is emerging as perhaps the most important mechanism through which the lifestyle-choices we make can directly influence the genome. Considerable epidemiological, experimental and clinical data have been amassed showing that the risk of developing disease in later life is dependent on early life conditions, mainly operating within the normative range of developmental exposures. In addition to the 'maternal' interactions, there has been increasing interest in the epigenetic mechanisms through which 'paternal' influences on offspring development can be achieved. Nutrition, among many other environmental factors, is a key player that can induce epigenetic changes not only in the directly exposed organisms but also in subsequent generations through the transgenerational inheritance of epigenetic traits. Overall, significant progress has been made in the field of epigenetics and obesity and the first potential epigenetic markers for obesity that could be detected at birth have been identified. Fortunately, epigenetic phenomena are dynamic and rather quickly reversible with intensive lifestyle changes. This is a very promising and sustainable resolution to the obesity pandemic.

  4. Epigenetic memory in mammals

    Directory of Open Access Journals (Sweden)

    Zoe eMigicovsky

    2011-06-01

    Full Text Available Epigenetic information can be passed on from one generation to another via DNA methylation, histone modifications and changes in small RNAs, a process called epigenetic memory. During a mammal’s lifecycle epigenetic reprogramming, or the resetting of most epigenetic marks, occurs twice. The first instance of reprogramming occurs in primordial germ cells and the second occurs following fertilization. These processes may be both passive and active. In order for epigenetic inheritance to occur the epigenetic modifications must be able to escape reprogramming. There are several examples supporting this non-Mendelian mechanism of inheritance including the prepacking of early developmental genes in histones instead of protamines in sperm, genomic imprinting via methylation marks, the retention of CenH3 in mammalian sperm and the inheritance of piwi-associated interfering RNAs. The ability of mammals to pass on epigenetic information to their progeny provides clear evidence that inheritance is not restricted to DNA sequence and epigenetics plays a key role in producing viable offspring.

  5. Recent developments in epigenetics of acute and chronic kidney diseases.

    Science.gov (United States)

    Reddy, Marpadga A; Natarajan, Rama

    2015-08-01

    The growing epidemic of obesity and diabetes, the aging population as well as prevalence of drug abuse has led to significant increases in the rates of the closely associated acute and chronic kidney diseases, including diabetic nephropathy. Furthermore, evidence shows that parental behavior and diet can affect the phenotype of subsequent generations via epigenetic transmission mechanisms. These data suggest a strong influence of the environment on disease susceptibility and that, apart from genetic susceptibility, epigenetic mechanisms need to be evaluated to gain critical new information about kidney diseases. Epigenetics is the study of processes that control gene expression and phenotype without alterations in the underlying DNA sequence. Epigenetic modifications, including cytosine DNA methylation and covalent post-translational modifications of histones in chromatin, are part of the epigenome, the interface between the stable genome and the variable environment. This dynamic epigenetic layer responds to external environmental cues to influence the expression of genes associated with disease states. The field of epigenetics has seen remarkable growth in the past few years with significant advances in basic biology, contributions to human disease, as well as epigenomics technologies. Further understanding of how the renal cell epigenome is altered by metabolic and other stimuli can yield novel new insights into the pathogenesis of kidney diseases. In this review, we have discussed the current knowledge on the role of epigenetic mechanisms (primarily DNAme and histone modifications) in acute and chronic kidney diseases, and their translational potential to identify much needed new therapies.

  6. Epigenetics and cancer

    DEFF Research Database (Denmark)

    Lund, Anders H; van Lohuizen, Maarten

    2004-01-01

    Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development. This is e......Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development....... This is evident from every aspect of tumor biology including cell growth and differentiation, cell cycle control, DNA repair, angiogenesis, migration, and evasion of host immunosurveillance. In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic...

  7. Elusive inheritance: Transgenerational effects and epigenetic inheritance in human environmental disease.

    Science.gov (United States)

    Martos, Suzanne N; Tang, Wan-Yee; Wang, Zhibin

    2015-07-01

    Epigenetic mechanisms involving DNA methylation, histone modification, histone variants and nucleosome positioning, and noncoding RNAs regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and DNA. Epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. The idea that environment-induced epigenetic changes in mammals could be inherited through the germline, independent of genetic mechanisms, has stimulated much debate. Many experimental models have been designed to interrogate the possibility of transgenerational epigenetic inheritance and provide insight into how environmental exposures influence phenotypes over multiple generations in the absence of any apparent genetic mutation. Unexpected molecular evidence has forced us to reevaluate not only our understanding of the plasticity and heritability of epigenetic factors, but of the stability of the genome as well. Recent reviews have described the difference between transgenerational and intergenerational effects; the two major epigenetic reprogramming events in the mammalian lifecycle; these two events making transgenerational epigenetic inheritance of environment-induced perturbations rare, if at all possible, in mammals; and mechanisms of transgenerational epigenetic inheritance in non-mammalian eukaryotic organisms. This paper briefly introduces these topics and mainly focuses on (1) transgenerational phenotypes and epigenetic effects in mammals, (2) environment-induced intergenerational epigenetic effects, and (3) the inherent difficulties in establishing a role for epigenetic inheritance in human environmental disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Phase retrieval from diffraction data utilizing pre-determined partial information

    International Nuclear Information System (INIS)

    Kim, S.S.; Marathe, S.; Kim, S.N.; Kang, H.C.; Noh, D.Y.

    2007-01-01

    We developed a phase retrieval algorithm that utilizes pre-determined partial phase information to overcome insufficient oversampling ratio in diffraction data. Implementing the Fourier modulus projection and the modified support projection manifesting the pre-determined information, a generalized difference map and HIO (Hybrid Input-Output) algorithms are developed. Optical laser diffraction data as well as simulated X-ray diffraction data are used to illustrate the validity of the proposed algorithm, which revealed the strength and the limitations of the algorithm. The proposed algorithm can expand the applicability of the diffraction based image reconstruction

  9. Effects of HRV-Guided vs. Predetermined Block Training on Performance, HRV and Serum Hormones.

    Science.gov (United States)

    Nuuttila, Olli-Pekka; Nikander, Aku; Polomoshnov, Dmitry; Laukkanen, Jari Antero; Häkkinen, Keijo

    2017-11-01

    The aim of this study was to compare heart rate variability -guided (HRVG) and predetermined (PD) block periodization of high intensity aerobic training (HIT). Endurance performance, neuromuscular performance, heart rate variability (HRV) and serum hormone concentrations were measured before, in the middle and after the 8-week training period in 24 endurance trained males. Both groups improved significantly maximal treadmill velocity (V max ) (pHRV (RMSSD, LF and TP) increased significantly only in HRVG (pHRV and serum testosterone levels observed in HRVG, individually HRV -guided block training may be more optimal compared to predetermined training. © Georg Thieme Verlag KG Stuttgart · New York.

  10. Scrutinizing the epigenetics revolution

    Science.gov (United States)

    Meloni, Maurizio; Testa, Giuseppe

    2014-01-01

    Epigenetics is one of the most rapidly expanding fields in the life sciences. Its rise is frequently framed as a revolutionary turn that heralds a new epoch both for gene-based epistemology and for the wider discourse on life that pervades knowledge-intensive societies of the molecular age. The fundamentals of this revolution remain however to be scrutinized, and indeed the very contours of what counts as ‘epigenetic' are often blurred. This is reflected also in the mounting discourse on the societal implications of epigenetics, in which vast expectations coexist with significant uncertainty about what aspects of this science are most relevant for politics or policy alike. This is therefore a suitable time to reflect on the directions that social theory could most productively take in the scrutiny of this revolution. Here we take this opportunity in both its scholarly and normative dimension, that is, proposing a roadmap for social theorizing on epigenetics that does not shy away from, and indeed hopefully guides, the framing of its most socially relevant outputs. To this end, we start with an epistemological reappraisal of epigenetic discourse that valorizes the blurring of meanings as a critical asset for the field and privileged analytical entry point. We then propose three paths of investigation. The first looks at the structuring elements of controversies and visions around epigenetics. The second probes the mutual constitution between the epigenetic reordering of living phenomena and the normative settlements that orient individual and collective responsibilities. The third highlights the material import of epigenetics and the molecularization of culture that it mediates. We suggest that these complementary strands provide both an epistemically and socially self-reflective framework to advance the study of epigenetics as a molecular juncture between nature and nurture and thus as the new critical frontier in the social studies of the life sciences. PMID

  11. Speciation, phenotypic variation and plasticity: what can endocrine disruptors tell us?

    Science.gov (United States)

    Ayala-García, Braulio; López-Santibáñez Guevara, Marta; Marcos-Camacho, Lluvia I; Fuentes-Farías, Alma L; Meléndez-Herrera, Esperanza; Gutiérrez-Ospina, Gabriel

    2013-01-01

    Phenotype variability, phenotypic plasticity, and the inheritance of phenotypic traits constitute the fundamental ground of processes such as individuation, individual and species adaptation and ultimately speciation. Even though traditional evolutionary thinking relies on genetic mutations as the main source of intra- and interspecies phenotypic variability, recent studies suggest that the epigenetic modulation of gene transcription and translation, epigenetic memory, and epigenetic inheritance are by far the most frequent reliable sources of transgenerational variability among viable individuals within and across organismal species. Therefore, individuation and speciation should be considered as nonmutational epigenetic phenomena.

  12. Speciation, Phenotypic Variation and Plasticity: What Can Endocrine Disruptors Tell Us?

    Directory of Open Access Journals (Sweden)

    Braulio Ayala-García

    2013-01-01

    Full Text Available Phenotype variability, phenotypic plasticity, and the inheritance of phenotypic traits constitute the fundamental ground of processes such as individuation, individual and species adaptation and ultimately speciation. Even though traditional evolutionary thinking relies on genetic mutations as the main source of intra- and interspecies phenotypic variability, recent studies suggest that the epigenetic modulation of gene transcription and translation, epigenetic memory, and epigenetic inheritance are by far the most frequent reliable sources of transgenerational variability among viable individuals within and across organismal species. Therefore, individuation and speciation should be considered as nonmutational epigenetic phenomena.

  13. Epigenetics and obesity.

    Science.gov (United States)

    Campión, Javier; Milagro, Fermin; Martínez, J Alfredo

    2010-01-01

    The etiology of obesity is multifactorial, involving complex interactions among the genetic makeup, neuroendocrine status, fetal programming, and different unhealthy environmental factors, such as sedentarism or inadequate dietary habits. Among the different mechanisms causing obesity, epigenetics, defined as the study of heritable changes in gene expression that occur without a change in the DNA sequence, has emerged as a very important determinant. Experimental evidence concerning dietary factors influencing obesity development through epigenetic mechanisms has been described. Thus, identification of those individuals who present with changes in DNA methylation profiles, certain histone modifications, or other epigenetically related processes could help to predict their susceptibility to gain or lose weight. Indeed, research concerning epigenetic mechanisms affecting weight homeostasis may play a role in the prevention of excessive fat deposition, the prediction of the most appropriate weight reduction plan, and the implementation of newer therapeutic approaches. Copyright © 2010 Elsevier Inc. All rights reserved.

  14. Eating Disorders and Epigenetics.

    Science.gov (United States)

    Thaler, Lea; Steiger, Howard

    2017-01-01

    Eating disorders (EDs) are characterized by intense preoccupation with shape and weight and maladaptive eating practices. The complex of symptoms that characterize EDs often arise through the activation of latent genetic potentials by environmental exposures, and epigenetic mechanisms are believed to link environmental exposures to gene expression. This chapter provides an overview of genetic factors acting in the etiology of EDs. It then provides a background to the hypothesis that epigenetic mechanisms link stresses such as obstetric complications and childhood abuse as well as effects of malnutrition to eating disorders (EDs). The chapter then summarizes the emerging body of literature on epigenetics and EDs-mainly studies on DNA methylation in samples of anorexia and bulimia. The available evidence base suggests that an epigenetically informed perspective contributes in valuable ways to the understanding of why people develop EDs.

  15. Whole Genome Epigenetics

    National Research Council Canada - National Science Library

    Carmell, Michelle A; Hannon, Gregory J

    2005-01-01

    .... Recently, several labs have published manuscripts identifying RNA interference as being crucial for the establishment of such epigenetic changes in species as diverse as Drosophila, plants, and the fission yeast S. pombe...

  16. Whole Genome Epigenetics

    National Research Council Canada - National Science Library

    Carmell, Michelle A; Hannon, Gregory J

    2004-01-01

    .... Recently, several labs have published manuscripts identifying RNA interference as being crucial for the establishment of such epigenetic changes in species as diverse as Drosophila, plants, and the fission yeast S. pombe...

  17. Whole Genome Epigenetics

    National Research Council Canada - National Science Library

    Carmell, Michelle

    2003-01-01

    .... Recently, several labs have published manuscripts identifying RNA interference as being crucial for the establishment of such epigenetic changes in species as diverse as Drosphilia, plants, and the fission yeast S. pombe...

  18. Whole Genome Epigenetics

    National Research Council Canada - National Science Library

    Carmell, Michelle A; Hannon, Gregory J

    2004-01-01

    .... However, this is only part of the picture. Increasingly, we are learning that epigenetic changes, that is, changes in chromatin structure, are critically important in regulating cellular gene expression...

  19. Whole Genome Epigenetics

    National Research Council Canada - National Science Library

    Carmell, Michelle A; Hannon, Gregory J

    2005-01-01

    .... However, this is only part of the picture. Increasingly, we are learning that epigenetic changes, that is, changes in chromatin structure, are critically important in regulating cellular gene expression...

  20. Whole Genome Epigenetics

    National Research Council Canada - National Science Library

    Carmell, Michelle

    2003-01-01

    .... However, this is only part of the picture. Increasingly, we are learning that epigenetic changes, that is, changes in chromatin structure, are critically important in regulation cellular gene expression...

  1. Epigenetics of host-pathogen interactions: the road ahead and the road behind.

    Directory of Open Access Journals (Sweden)

    Elena Gómez-Díaz

    Full Text Available A growing body of evidence points towards epigenetic mechanisms being responsible for a wide range of biological phenomena, from the plasticity of plant growth and development to the nutritional control of caste determination in honeybees and the etiology of human disease (e.g., cancer. With the (partial elucidation of the molecular basis of epigenetic variation and the heritability of certain of these changes, the field of evolutionary epigenetics is flourishing. Despite this, the role of epigenetics in shaping host-pathogen interactions has received comparatively little attention. Yet there is plenty of evidence supporting the implication of epigenetic mechanisms in the modulation of the biological interaction between hosts and pathogens. The phenotypic plasticity of many key parasite life-history traits appears to be under epigenetic control. Moreover, pathogen-induced effects in host phenotype may have transgenerational consequences, and the bases of these changes and their heritability probably have an epigenetic component. The significance of epigenetic modifications may, however, go beyond providing a mechanistic basis for host and pathogen plasticity. Epigenetic epidemiology has recently emerged as a promising area for future research on infectious diseases. In addition, the incorporation of epigenetic inheritance and epigenetic plasticity mechanisms to evolutionary models and empirical studies of host-pathogen interactions will provide new insights into the evolution and coevolution of these associations. Here, we review the evidence available for the role epigenetics on host-pathogen interactions, and the utility and versatility of the epigenetic technologies available that can be cross-applied to host-pathogen studies. We conclude with recommendations and directions for future research on the burgeoning field of epigenetics as applied to host-pathogen interactions.

  2. Epigenetics and Cellular Metabolism

    OpenAIRE

    Wenyi Xu; Fengzhong Wang; Zhongsheng Yu; Fengjiao Xin

    2016-01-01

    Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the proce...

  3. Epigenetics in Prostate Cancer

    OpenAIRE

    Albany, Costantine; Alva, Ajjai S.; Aparicio, Ana M.; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M.

    2011-01-01

    Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequ...

  4. Epigenetic Alterations in Fanconi Anaemia: Role in Pathophysiology and Therapeutic Potential.

    Directory of Open Access Journals (Sweden)

    Hélio Belo

    Full Text Available Fanconi anaemia (FA is an inherited disorder characterized by chromosomal instability. The phenotype is variable, which raises the possibility that it may be affected by other factors, such as epigenetic modifications. These play an important role in oncogenesis and may be pharmacologically manipulated. Our aim was to explore whether the epigenetic profiles in FA differ from non-FA individuals and whether these could be manipulated to alter the disease phenotype. We compared expression of epigenetic genes and DNA methylation profile of tumour suppressor genes between FA and normal samples. FA samples exhibited decreased expression levels of genes involved in epigenetic regulation and hypomethylation in the promoter regions of tumour suppressor genes. Treatment of FA cells with histone deacetylase inhibitor Vorinostat increased the expression of DNM3Tβ and reduced the levels of CIITA and HDAC9, PAK1, USP16, all involved in different aspects of epigenetic and immune regulation. Given the ability of Vorinostat to modulate epigenetic genes in FA patients, we investigated its functional effects on the FA phenotype. This was assessed by incubating FA cells with Vorinostat and quantifying chromosomal breaks induced by DNA cross-linking agents. Treatment of FA cells with Vorinostat resulted in a significant reduction of aberrant cells (81% on average. Our results suggest that epigenetic mechanisms may play a role in oncogenesis in FA. Epigenetic agents may be helpful in improving the phenotype of FA patients, potentially reducing tumour incidence in this population.

  5. Daddy issues: paternal effects on phenotype.

    Science.gov (United States)

    Rando, Oliver J

    2012-11-09

    The once popular and then heretical idea that ancestral environment can affect the phenotype of future generations is coming back into vogue due to advances in the field of epigenetic inheritance. How paternal environmental conditions influence the phenotype of progeny is now a tractable question, and researchers are exploring potential mechanisms underlying such effects. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Epigenetics of reproductive infertility.

    Science.gov (United States)

    Das, Laxmidhar; Parbin, Sabnam; Pradhan, Nibedita; Kausar, Chahat; Patra, Samir K

    2017-06-01

    Infertility is a complex pathophysiological condition. It may caused by specific or multiple physical and physiological factors, including abnormalities in homeostasis, hormonal imbalances and genetic alterations. In recent times various studies implicated that, aberrant epigenetic mechanisms are associated with reproductive infertility. There might be transgenerational effects associated with epigenetic modifications of gametes and studies suggest the importance of alterations in epigenetic modification at early and late stages of gametogenesis. To determine the causes of infertility it is necessary to understand the altered epigenetic modifications of associated gene and mechanisms involved therein. This review is devoted to elucidate the recent mechanistic advances in regulation of genes by epigenetic modification and emphasizes their possible role related to reproductive infertility. It includes environmental, nutritional, hormonal and physiological factors and influence of internal structural architecture of chromatin nucleosomes affecting DNA and histone modifications in both male and female gametes, early embryogenesis and offspring. Finally, we would like to emphasize that research on human infertility by gene knock out of epigenetic modifiers genes must be relied upon animal models.

  7. [Epigenetics 2.0: The multiple faces of the genome].

    Science.gov (United States)

    Rubinstein, Marcelo

    2016-09-01

    Epigenetics is the branch of genetics that studies the dynamic relationship between stable genotypes and varying phenotypes. To this end, epigenetics aims to discover the molecular mechanisms that explain how different nutrients and hormones, environmental changes, and emotional, social and cognitive experiences modify gene expression and behaviors, even permanently so. Psychiatry has learned that diseases with strong genetic predisposition, such as schizophrenia, show a concordance of around 50% between monozygotic twins, thus evidencing the importance of the genetic background and the presence of environmental variables that stimulate or block phenotypic development. The interest in epigenetics has increased during the last few years due to fundamental discoveries made in molecular and behavioral genetics, although within this framework factual knowledge coexists with fictional expectations and wrong concepts. Is it possible that epigenetic variants modify temperament and human behavior? May abused or neglected children develop long-lasting epigenetic marks in their DNA? May bipolar states correlate with different epigenetic signatures? Studying these subjects in not an easy task, but experiments performed in lab animals suggest that these conjectures are reasonable, although there is still a long distance between hypotheses and scientifically proven facts.

  8. Natural epigenetic variation contributes to heritable flowering divergence in a widespread asexual dandelion lineage

    NARCIS (Netherlands)

    Wilschut, R.A.; Oplaat, C.; Snoek, B.; Kirschner, J.; Verhoeven, K.J.F.

    2016-01-01

    Epigenetic variation has been proposed to contribute to the success of asexual plants, either as a contributor to phenotypic plasticity or by enabling transient adaptation via selection on transgenerationally stable, but reversible, epialleles. While recent studies in experimental plant populations

  9. Data from: Natural epigenetic variation contributes to heritable flowering divergence in a widespread asexual dandelion lineage

    NARCIS (Netherlands)

    Wilschut, Rutger; Oplaat, C.; Snoek, L.B.; Kirschner, J.; Verhoeven, K.J.F.

    2015-01-01

    Epigenetic variation has been proposed to contribute to the success of asexual plants, either as a contributor to phenotypic plasticity or by enabling transient adaptation via selection on transgenerationally stable, but reversible, epialleles. While recent studies in experimental plant populations

  10. Salmon and steelhead genetics and genomics - Epigenetic and genomic variation in salmon and steelhead

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Conduct analyses of epigenetic and genomic variation in Chinook salmon and steelhead to determine influence on phenotypic expression of life history traits. Genetic,...

  11. Genetics and epigenetics of rheumatoid arthritis

    Science.gov (United States)

    Viatte, Sebastien; Plant, Darren; Raychaudhuri, Soumya

    2013-01-01

    Investigators have made key advances in rheumatoid arthritis (RA) genetics in the past 10 years. Although genetic studies have had limited influence on clinical practice and drug discovery, they are currently generating testable hypotheses to explain disease pathogenesis. Firstly, we review here the major advances in identifying RA genetic susceptibility markers both within and outside of the MHC. Understanding how genetic variants translate into pathogenic mechanisms and ultimately into phenotypes remains a mystery for most of the polymorphisms that confer susceptibility to RA, but functional data are emerging. Interplay between environmental and genetic factors is poorly understood and in need of further investigation. Secondly, we review current knowledge of the role of epigenetics in RA susceptibility. Differences in the epigenome could represent one of the ways in which environmental exposures translate into phenotypic outcomes. The best understood epigenetic phenomena include post-translational histone modifications and DNA methylation events, both of which have critical roles in gene regulation. Epigenetic studies in RA represent a new area of research with the potential to answer unsolved questions. PMID:23381558

  12. Bifurcation in epigenetics: Implications in development, proliferation, and diseases

    Science.gov (United States)

    Jost, Daniel

    2014-01-01

    Cells often exhibit different and stable phenotypes from the same DNA sequence. Robustness and plasticity of such cellular states are controlled by diverse transcriptional and epigenetic mechanisms, among them the modification of biochemical marks on chromatin. Here, we develop a stochastic model that describes the dynamics of epigenetic marks along a given DNA region. Through mathematical analysis, we show the emergence of bistable and persistent epigenetic states from the cooperative recruitment of modifying enzymes. We also find that the dynamical system exhibits a critical point and displays, in the presence of asymmetries in recruitment, a bifurcation diagram with hysteresis. These results have deep implications for our understanding of epigenetic regulation. In particular, our study allows one to reconcile within the same formalism the robust maintenance of epigenetic identity observed in differentiated cells, the epigenetic plasticity of pluripotent cells during differentiation, and the effects of epigenetic misregulation in diseases. Moreover, it suggests a possible mechanism for developmental transitions where the system is shifted close to the critical point to benefit from high susceptibility to developmental cues.

  13. Epigenetic developmental programs and adipogenesis: implications for psychotropic induced obesity.

    Science.gov (United States)

    Chase, Kayla; Sharma, Rajiv P

    2013-11-01

    Psychotropic agents are notorious for their ability to increase fat mass in psychiatric patients. The two determinants of fat mass are the production of newly differentiated adipocytes (adipogenesis), and the volume of lipid accumulation. Epigenetic programs have a prominent role in cell fate commitments and differentiation required for adipogenesis. In parallel, epigenetic effects on energy metabolism are well supported by several genetic models. Consequently, a variety of psychotropics, often prescribed in combinations and for long periods, may utilize a common epigenetic effector path causing an increase in adipogenesis or reduction in energy metabolism. In particular, the recent discovery that G protein coupled signaling cascades can directly modify epigenetic regulatory enzymes implicates surface receptor activity by psychotropic medications. The potential therapeutic implications are also suggested by the effects of the clinically approved antidepressant tranylcypromine, also a histone demethylase inhibitor, which has impressive therapeutic effects on metabolism in the obese phenotype.

  14. Epigenetic control of CD8+ T cell differentiation.

    Science.gov (United States)

    Henning, Amanda N; Roychoudhuri, Rahul; Restifo, Nicholas P

    2018-05-01

    Upon stimulation, small numbers of naive CD8 + T cells proliferate and differentiate into a variety of memory and effector cell types. CD8 + T cells can persist for years and kill tumour cells and virally infected cells. The functional and phenotypic changes that occur during CD8 + T cell differentiation are well characterized, but the epigenetic states that underlie these changes are incompletely understood. Here, we review the epigenetic processes that direct CD8 + T cell differentiation and function. We focus on epigenetic modification of DNA and associated histones at genes and their regulatory elements. We also describe structural changes in chromatin organization that affect gene expression. Finally, we examine the translational potential of epigenetic interventions to improve CD8 + T cell function in individuals with chronic infections and cancer.

  15. Chromatin remodelling and epigenetic state regulation by non-coding RNAs in the diseased heart

    OpenAIRE

    F. De Majo; M. Calore

    2018-01-01

    Epigenetics refers to all the changes in phenotype and gene expression which are not due to alterations in the DNA sequence. These mechanisms have a pivotal role not only in the development but also in the maintenance during adulthood of a physiological phenotype of the heart. Because of the crucial role of epigenetic modifications, their alteration can lead to the arise of pathological conditions.Heart failure affects an estimated 23 million people worldwide and leads to substantial numbers ...

  16. Epigenetics of Obesity.

    Science.gov (United States)

    Lopomo, A; Burgio, E; Migliore, L

    2016-01-01

    Obesity is a metabolic disease, which is becoming an epidemic health problem: it has been recently defined in terms of Global Pandemic. Over the years, the approaches through family, twins and adoption studies led to the identification of some causal genes in monogenic forms of obesity but the origins of the pandemic of obesity cannot be considered essentially due to genetic factors, because human genome is not likely to change in just a few years. Epigenetic studies have offered in recent years valuable tools for the understanding of the worldwide spread of the pandemic of obesity. The involvement of epigenetic modifications-DNA methylation, histone tails, and miRNAs modifications-in the development of obesity is more and more evident. In the epigenetic literature, there are evidences that the entire embryo-fetal and perinatal period of development plays a key role in the programming of all human organs and tissues. Therefore, the molecular mechanisms involved in the epigenetic programming require a new and general pathogenic paradigm, the Developmental Origins of Health and Disease theory, to explain the current epidemiological transition, that is, the worldwide increase of chronic, degenerative, and inflammatory diseases such as obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. Obesity and its related complications are more and more associated with environmental pollutants (obesogens), gut microbiota modifications and unbalanced food intake, which can induce, through epigenetic mechanisms, weight gain, and altered metabolic consequences. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. The physics of epigenetics

    Science.gov (United States)

    Cortini, Ruggero; Barbi, Maria; Caré, Bertrand R.; Lavelle, Christophe; Lesne, Annick; Mozziconacci, Julien; Victor, Jean-Marc

    2016-04-01

    In higher organisms, all cells share the same genome, but every cell expresses only a limited and specific set of genes that defines the cell type. During cell division, not only the genome, but also the cell type is inherited by the daughter cells. This intriguing phenomenon is achieved by a variety of processes that have been collectively termed epigenetics: the stable and inheritable changes in gene expression patterns. This article reviews the extremely rich and exquisitely multiscale physical mechanisms that govern the biological processes behind the initiation, spreading, and inheritance of epigenetic states. These include not only the changes in the molecular properties associated with the chemical modifications of DNA and histone proteins, such as methylation and acetylation, but also less conventional changes, typically in the physics that governs the three-dimensional organization of the genome in cell nuclei. Strikingly, to achieve stability and heritability of epigenetic states, cells take advantage of many different physical principles, such as the universal behavior of polymers and copolymers, the general features of dynamical systems, and the electrostatic and mechanical properties related to chemical modifications of DNA and histones. By putting the complex biological literature in this new light, the emerging picture is that a limited set of general physical rules play a key role in initiating, shaping, and transmitting this crucial "epigenetic landscape." This new perspective not only allows one to rationalize the normal cellular functions, but also helps to understand the emergence of pathological states, in which the epigenetic landscape becomes dysfunctional.

  18. The emergence of business model for digital innovation projects without predetermined usage and market potential

    OpenAIRE

    Antonopoulou, Katerina; Nandhakumar, Joe; Begkos, Christos

    2016-01-01

    In this paper we explore the emergence of business model for digital innovation projects without predetermined usage and uncertain market potential. We studied a firm, which was producing and launching digital platforms for managing organizational operations. Drawing on a case study of developing this digital platform, we identified three recurring calculative and narrative practices: ideating; concocting; aligning. We argue that through these practices various epistemic objects (which we cal...

  19. Epigenetic silencing of serine protease HTRA1 drives polyploidy

    International Nuclear Information System (INIS)

    Schmidt, Nina; Irle, Inga; Ripkens, Kamilla; Lux, Vanda; Nelles, Jasmin; Johannes, Christian; Parry, Lee; Greenow, Kirsty; Amir, Sarah; Campioni, Mara; Baldi, Alfonso; Oka, Chio; Kawaichi, Masashi; Clarke, Alan R.; Ehrmann, Michael

    2016-01-01

    Increased numbers and improperly positioned centrosomes, aneuploidy or polyploidy, and chromosomal instability are frequently observed characteristics of cancer cells. While some aspects of these events and the checkpoint mechanisms are well studied, not all players have yet been identified. As the role of proteases other than the proteasome in tumorigenesis is an insufficiently addressed question, we investigated the epigenetic control of the widely conserved protease HTRA1 and the phenotypes of deregulation. Mouse embryonal fibroblasts and HCT116 and SW480 cells were used to study the mechanism of epigenetic silencing of HTRA1. In addition, using cell biological and genetic methods, the phenotypes of downregulation of HTRA1 expression were investigated. HTRA1 is epigenetically silenced in HCT116 colon carcinoma cells via the epigenetic adaptor protein MBD2. On the cellular level, HTRA1 depletion causes multiple phenotypes including acceleration of cell growth, centrosome amplification and polyploidy in SW480 colon adenocarcinoma cells as well as in primary mouse embryonic fibroblasts (MEFs). Downregulation of HTRA1 causes a number of phenotypes that are hallmarks of cancer cells suggesting that the methylation state of the HtrA1 promoter may be used as a biomarker for tumour cells or cells at risk of transformation. The online version of this article (doi:10.1186/s12885-016-2425-8) contains supplementary material, which is available to authorized users

  20. Epigenetics and the Biological Definition of Gene X Environment Interactions

    Science.gov (United States)

    Meaney, Michael J.

    2010-01-01

    Variations in phenotype reflect the influence of environmental conditions during development on cellular functions, including that of the genome. The recent integration of epigenetics into developmental psychobiology illustrates the processes by which environmental conditions in early life structurally alter DNA, providing a physical basis for the…

  1. Epigenetics and assisted reproductive technologies

    DEFF Research Database (Denmark)

    Pinborg, Anja; Loft, Anne; Romundstad, Liv Bente

    2016-01-01

    Epigenetic modification controls gene activity without changes in the DNA sequence. The genome undergoes several phases of epigenetic programming during gametogenesis and early embryo development coinciding with assisted reproductive technologies (ART) treatments. Imprinting disorders have been...

  2. Epigenetics and lifestyle.

    Science.gov (United States)

    Alegría-Torres, Jorge Alejandro; Baccarelli, Andrea; Bollati, Valentina

    2011-06-01

    The concept of 'lifestyle' includes different factors such as nutrition, behavior, stress, physical activity, working habits, smoking and alcohol consumption. Increasing evidence shows that environmental and lifestyle factors may influence epigenetic mechanisms, such as DNA methylation, histone acetylation and miRNA expression. It has been identified that several lifestyle factors such as diet, obesity, physical activity, tobacco smoking, alcohol consumption, environmental pollutants, psychological stress and working on night shifts might modify epigenetic patterns. Most of the studies conducted so far have been centered on DNA methylation, whereas only a few investigations have studied lifestyle factors in relation to histone modifications and miRNAs. This article reviews current evidence indicating that lifestyle factors might affect human health via epigenetic mechanisms.

  3. Anxiety and Epigenetics.

    Science.gov (United States)

    Bartlett, Andrew A; Singh, Rumani; Hunter, Richard G

    2017-01-01

    Anxiety disorders are highly prevalent psychiatric disorders often comorbid with depression and substance abuse. Twin studies have shown that anxiety disorders are moderately heritable. Yet, genome-wide association studies (GWASs) have failed to identify gene(s) significantly associated with diagnosis suggesting a strong role for environmental factors and the epigenome. A number of anxiety disorder subtypes are considered "stress related." A large focus of research has been on the epigenetic and anxiety-like behavioral consequences of stress. Animal models of anxiety-related disorders have provided strong evidence for the role of stress on the epigenetic control of the hypothalamic-pituitary-adrenal (HPA) axis and of stress-responsive brain regions. Neuroepigenetics may continue to explain individual variation in susceptibility to environmental perturbations and consequently anxious behavior. Behavioral and pharmacological interventions aimed at targeting epigenetic marks associated with anxiety may prove fruitful in developing treatments.

  4. Epigenetics in prostate cancer.

    Science.gov (United States)

    Albany, Costantine; Alva, Ajjai S; Aparicio, Ana M; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M

    2011-01-01

    Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a "normal" epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  5. Epigenetics in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Costantine Albany

    2011-01-01

    Full Text Available Prostate cancer (PC is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  6. Epigenetics and cerebral organoids

    DEFF Research Database (Denmark)

    Forsberg, Sheena Louise; Ilieva, Mirolyuba; Maria Michel, Tanja

    2018-01-01

    also play a role. Some studies indicate a set of candidate genes with different DNA methylation profiles in ASD compared to healthy individuals. Thus epigenetic alterations could help bridging the gene-environment gap in deciphering the underlying neurobiology of autism. However, epigenome......-wide association studies (EWAS) have mainly included a very limited number of postmortem brain samples. Hence, cellular models mimicking brain development in vitro will be of great importance to study the critical epigenetic alterations and when they might happen. This review will give an overview of the state...... of the art concerning knowledge on epigenetic changes in autism and how new, cutting edge expertise based on three-dimensional (3D) stem cell technology models (brain organoids) can contribute in elucidating the multiple aspects of disease mechanisms....

  7. How stable 'should' epigenetic modifications be? Insights from adaptive plasticity and bet hedging.

    Science.gov (United States)

    Herman, Jacob J; Spencer, Hamish G; Donohue, Kathleen; Sultan, Sonia E

    2014-03-01

    Although there is keen interest in the potential adaptive value of epigenetic variation, it is unclear what conditions favor the stability of these variants either within or across generations. Because epigenetic modifications can be environmentally sensitive, existing theory on adaptive phenotypic plasticity provides relevant insights. Our consideration of this theory suggests that stable maintenance of environmentally induced epigenetic states over an organism's lifetime is most likely to be favored when the organism accurately responds to a single environmental change that subsequently remains constant, or when the environmental change cues an irreversible developmental transition. Stable transmission of adaptive epigenetic states from parents to offspring may be selectively favored when environments vary across generations and the parental environment predicts the offspring environment. The adaptive value of stability beyond a single generation of parent-offspring transmission likely depends on the costs of epigenetic resetting. Epigenetic stability both within and across generations will also depend on the degree and predictability of environmental variation, dispersal patterns, and the (epi)genetic architecture underlying phenotypic responses to environment. We also discuss conditions that favor stability of random epigenetic variants within the context of bet hedging. We conclude by proposing research directions to clarify the adaptive significance of epigenetic stability. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

  8. Epigenetic Therapy in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Stephen V Liu

    2013-05-01

    Full Text Available Epigenetic dysregulation of gene function has been strongly implicated in carcinogenesis and is one of the mechanisms contributing to the development of lung cancer. The inherent reversibility of epigenetic alterations makes them viable therapeutic targets. Here, we review the therapeutic implications of epigenetic changes in lung cancer, and recent advances in therapeutic strategies targeting DNA methylation and histone acetylation.

  9. Epigenetics in plant tissue culture

    NARCIS (Netherlands)

    Smulders, M.J.M.; Klerk, de G.J.M.

    2011-01-01

    Plants produced vegetatively in tissue culture may differ from the plants from which they have been derived. Two major classes of off-types occur: genetic ones and epigenetic ones. This review is about epigenetic aberrations. We discuss recent studies that have uncovered epigenetic modifications at

  10. Evolution, epigenetics and cooperation

    Indian Academy of Sciences (India)

    Explanations for biological evolution in terms of changes in gene frequencies refer to outcomes rather than process. Integrating epigenetic studies with older evolutionary theories has drawn attention to the ways in which evolution occurs. Adaptation at the level of the gene is givingway to adaptation at the level of the ...

  11. Epigenetic changes in myelofibrosis

    DEFF Research Database (Denmark)

    Nielsen, Helene Myrtue; Andersen, Christen Lykkegaard; Westman, Maj

    2017-01-01

    , in 'inflammatory disease' in MF mononuclear cells, and in 'immunological diseases' in MF granulocytes. Only few differentially methylated CpG sites were common among the three cell populations. Mutations in the epigenetic regulators ASXL1 (47%) and TET2 (20%) were not associated with a specific DNA methylation...

  12. The epigenetics of obesity

    Science.gov (United States)

    Maternal nutrition at the time of conception and during pregnancy is considered a factor for individual differences in having obesity. The mechanisms underlying this association are likely partially epigenetic in nature, but pinning down the exact nature, location, and timing of these changes remain...

  13. Quantum cryptography with a predetermined key, using continuous-variable Einstein-Podolsky-Rosen correlations

    Science.gov (United States)

    Reid, M. D.

    2000-12-01

    Correlations of the type discussed by EPR in their original 1935 paradox for continuous variables exist for the quadrature phase amplitudes of two spatially separated fields. These correlations were first experimentally reported in 1992. We propose to use such EPR beams in quantum cryptography, to transmit with high efficiency messages in such a way that the receiver and sender may later determine whether eavesdropping has occurred. The merit of the new proposal is in the possibility of transmitting a reasonably secure yet predetermined key. This would allow relay of a cryptographic key over long distances in the presence of lossy channels.

  14. A modified palatal crib appliance for children with predetermined thumb-sucking habit - Case report

    International Nuclear Information System (INIS)

    AlEmran, Sulaiman

    2008-01-01

    The aim of this case report was to introduce a modified design of palatal crib habit breaking appliance that can be used for children with predetermined thumb-sucking habit. The appliance is made of two bands on the upper first permanent molars and an extended metal framework to cover the anterior of the palatal roof. The appliance was applied for 4 months on an 8-year-old boy who persistently continued the habit of thumb-sucking. The appliance proved to be very effective for arresting thumb-sucking habit. (author)

  15. Epigenetic modifications in prostate cancer.

    Science.gov (United States)

    Ngollo, Marjolaine; Dagdemir, Aslihan; Karsli-Ceppioglu, Seher; Judes, Gaelle; Pajon, Amaury; Penault-Llorca, Frederique; Boiteux, Jean-Paul; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique J

    2014-01-01

    Prostate cancer is the most common cancer in men and the second leading cause of cancer deaths in men in France. Apart from the genetic alterations in prostate cancer, epigenetics modifications are involved in the development and progression of this disease. Epigenetic events are the main cause in gene regulation and the three most epigenetic mechanisms studied include DNA methylation, histone modifications and microRNA expression. In this review, we summarized epigenetic mechanisms in prostate cancer. Epigenetic drugs that inhibit DNA methylation, histone methylation and histone acetylation might be able to reactivate silenced gene expression in prostate cancer. However, further understanding of interactions of these enzymes and their effects on transcription regulation in prostate cancer is needed and has become a priority in biomedical research. In this study, we summed up epigenetic changes with emphasis on pharmacologic epigenetic target agents.

  16. Epigenetics in Alzheimer's Disease: Perspective of DNA Methylation.

    Science.gov (United States)

    Qazi, Talal Jamil; Quan, Zhenzhen; Mir, Asif; Qing, Hong

    2018-02-01

    Research over the years has shown that causes of Alzheimer's disease are not well understood, but over the past years, the involvement of epigenetic mechanisms in the developing memory formation either under pathological or physiological conditions has become clear. The term epigenetics represents the heredity of changes in phenotype that are independent of altered DNA sequences. Different studies validated that cytosine methylation of genomic DNA decreases with age in different tissues of mammals, and therefore, the role of epigenetic factors in developing neurological disorders in aging has been under focus. In this review, we summarized and reviewed the involvement of different epigenetic mechanisms especially the DNA methylation in Alzheimer's disease (AD), late-onset Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and autosomal dominant Alzheimer's disease (ADAD). Down to the minutest of details, we tried to discuss the methylation patterns like mitochondrial DNA methylation and ribosomal DNA (rDNA) methylation. Additionally, we mentioned some therapeutic approaches related to epigenetics, which could provide a potential cure for AD. Moreover, we reviewed some recent studies that validate DNA methylation as a potential biomarker and its role in AD. We hope that this review will provide new insights into the understanding of AD pathogenesis from the epigenetic perspective especially from the perspective of DNA methylation.

  17. Transgenic Epigenetics: Using Transgenic Organisms to Examine Epigenetic Phenomena

    Directory of Open Access Journals (Sweden)

    Lori A. McEachern

    2012-01-01

    Full Text Available Non-model organisms are generally more difficult and/or time consuming to work with than model organisms. In addition, epigenetic analysis of model organisms is facilitated by well-established protocols, and commercially-available reagents and kits that may not be available for, or previously tested on, non-model organisms. Given the evolutionary conservation and widespread nature of many epigenetic mechanisms, a powerful method to analyze epigenetic phenomena from non-model organisms would be to use transgenic model organisms containing an epigenetic region of interest from the non-model. Interestingly, while transgenic Drosophila and mice have provided significant insight into the molecular mechanisms and evolutionary conservation of the epigenetic processes that target epigenetic control regions in other model organisms, this method has so far been under-exploited for non-model organism epigenetic analysis. This paper details several experiments that have examined the epigenetic processes of genomic imprinting and paramutation, by transferring an epigenetic control region from one model organism to another. These cross-species experiments demonstrate that valuable insight into both the molecular mechanisms and evolutionary conservation of epigenetic processes may be obtained via transgenic experiments, which can then be used to guide further investigations and experiments in the species of interest.

  18. Epigenetic codes programming class switch recombination

    Directory of Open Access Journals (Sweden)

    Bharat eVaidyanathan

    2015-09-01

    Full Text Available Class switch recombination imparts B cells with a fitness-associated adaptive advantage during a humoral immune response by using a precision-tailored DNA excision and ligation process to swap the default constant region gene of the antibody with a new one that has unique effector functions. This secondary diversification of the antibody repertoire is a hallmark of the adaptability of B cells when confronted with environmental and pathogenic challenges. Given that the nucleotide sequence of genes during class switching remains unchanged (genetic constraints, it is logical and necessary therefore, to integrate the adaptability of B cells to an epigenetic state, which is dynamic and can be heritably modulated before, after or even during an antibody-dependent immune response. Epigenetic regulation encompasses heritable changes that affect function (phenotype without altering the sequence information embedded in a gene, and include histone, DNA and RNA modifications. Here, we review current literature on how B cells use an epigenetic code language as a means to ensure antibody plasticity in light of pathogenic insults.

  19. [Early attachement relationships and epigenetic customization].

    Science.gov (United States)

    Rocchi, Giordana; Serio, Valentina; Carluccio, Giuseppe Mattia; Marini, Isabella; Meuti, Valentina; Zaccagni, Michela; Giacchetti, Nicoletta; Aceti, Franca

    2015-01-01

    Recently, new findings in epigenetic science switched the focus from the observation of physiological intragenomic dynamics to the idea of an environmental co-construction of phenotypic expression. In psichodynamic field, objectual relations and attachement theoreticians emphasized the interpersonal dimension of individual development, focusing the attention on the relational matrix of self organization. The construction of stable affective-behavioral traits throughout different parenting styles has actually found a coincidence in ethological studies, which have explored the epigenetic processes underlying the relationship between caregiving and HPA stress responsiveness. An adequate parenting style seems to support affective regulation throughout psychobiological hidden moderators, which would tend to rebalance the physiological systems homeostasis; an unconfident attachment style would promote, on the other hand, the allostatic load rise. Sites of longlife epigenetic susceptibility have also been identified in humans; although associated with risk of maladaptive developing in adverse environmental conditions, they seem to confer protection under favorable conditions. This persisting possibility of reorganization of stable traits throughout lifetime, which seems to be activated by a relevant environmental input, grant to significant relationships, and to therapeutical one as well, an implicit reconditioning potential which could result into the configuration of new stable affective-behavioral styles.

  20. Theory for the stability and regulation of epigenetic landscapes

    International Nuclear Information System (INIS)

    Micheelsen, Mille A; Mitarai, Namiko; Sneppen, Kim; Dodd, Ian B

    2010-01-01

    Cells can often choose among several stably heritable phenotypes. Examples are the expressions of genes in eukaryotic cells where long chromosomal regions can adopt persistent and heritable silenced or active states that may be associated with positive feedback in dynamic modification of nucleosomes. We generalize this mechanism in terms of bistability associated with valleys in an epigenetic landscape. A transfer matrix method was used to rigorously follow the system through the disruptive process of cell division. This combined treatment of noisy dynamics both between and during cell division provides an efficient way to calculate the stability of alternative states in a broad range of epigenetic systems

  1. Graft fixation with predetermined tension using a new device, the double spike plate.

    Science.gov (United States)

    Shino, Konsei; Mae, Tatsuo; Maeda, Akira; Miyama, Takahide; Shinjo, Hirotaka; Kawakami, Hideo

    2002-10-01

    To biomechanically evaluate a new fixation device, DSP (Double Spike Plate; Meira Corp, Nagoya, Aichi, Japan), for pullout graft fixation. Biomechanical study. A porcine tibia in which 8-mm diameter drill holes had been made from the medial tibial metaphysis to the anterior cruciate ligament attachment was rigidly fixed to a tension analyzer. A quadrupled graft consisting of 2 double-looped bovine tendons was prepared with No. 3 polyester sutures placed distally. The graft was passed through the drill hole, and its proximal loop ends were rigidly fixed to a load cell for monitoring graft tension. The graft's distal ends were connected to the DSP by tying the sutures to the top hole in the DSP. The graft tension was predetermined at 49 N (n = 5) or 98 N (n = 5). This tension was maintained for 5 minutes with a suture passed through the bottom hole of the DSP. The plate was fixed to the tibia by hammering its spikes into the bone under the index tension. Finally, the fixation was completed by inserting a screw. Although the graft tension immediately increased to 69 +/- 11 N or 133 +/- 14 N during hammering, it gradually reduced to 49 +/- 10 N or 100 +/- 7 N 5 minutes later. This study shows that graft fixation under a predetermined tension can be achieved with the DSP.

  2. Comparative epigenetic and genetic spatial structure of the perennial herb Helleborus foetidus: Isolation by environment, isolation by distance, and functional trait divergence.

    Science.gov (United States)

    Herrera, Carlos M; Medrano, Mónica; Bazaga, Pilar

    2017-08-16

    Epigenetic variation can play a role in local adaptation; thus, there should be associations among epigenetic variation, environmental variation, and functional trait variation across populations. This study examines these relationships in the perennial herb Helleborus foetidus (Ranunculaceae). Plants from 10 subpopulations were characterized genetically (AFLP, SSR markers), epigenetically (MSAP markers), and phenotypically (20 functional traits). Habitats were characterized using six environmental variables. Isolation-by-distance (IBD) and isolation-by-environment (IBE) patterns of genetic and epigenetic divergence were assessed, as was the comparative explanatory value of geographical and environmental distance as predictors of epigenetic, genetic, and functional differentiation. Subpopulations were differentiated genetically, epigenetically, and phenotypically. Genetic differentiation was best explained by geographical distance, while epigenetic differentiation was best explained by environmental distance. Divergence in functional traits was correlated with environmental and epigenetic distances, but not with geographical and genetic distances. Results are compatible with the hypothesis that epigenetic IBE and functional divergence reflected responses to environmental variation. Spatial analyses simultaneously considering epigenetic, genetic, phenotypic and environmental information provide a useful tool to evaluate the role of environmental features as drivers of natural epigenetic variation between populations. © 2017 Botanical Society of America.

  3. Epigenetic mechanisms in schizophrenia.

    Science.gov (United States)

    Akbarian, Schahram

    2014-09-01

    Schizophrenia is a major psychiatric disorder that lacks a unifying neuropathology, while currently available pharmacological treatments provide only limited benefits to many patients. This review will discuss how the field of neuroepigenetics could contribute to advancements of the existing knowledge on the neurobiology and treatment of psychosis. Genome-scale mapping of DMA methylation, histone modifications and variants, and chromosomal loopings for promoter-enhancer interactions and other epigenetic determinants of genome organization and function are likely to provide important clues about mechanisms contributing to dysregulated expression of synaptic and metabolic genes in schizophrenia brain, including the potential links to the underlying genetic risk architecture and environmental exposures. In addition, studies in animal models are providing a rapidly increasing list of chromatin-regulatory mechanisms with significant effects on cognition and complex behaviors, thereby pointing to the therapeutic potential of epigenetic drug targets in the nervous system.

  4. [Epigenetics of prostate cancer].

    Science.gov (United States)

    Yi, Xiao-Ming; Zhou, Wen-Quan

    2010-07-01

    Prostate cancer is one of the most common malignant tumors in males, and its etiology and pathogenesis remain unclear. Epigenesis is involved in prostate cancer at all stages of the process, and closely related with its growth and metastasis. DNA methylation and histone modification are the most important manifestations of epigenetics in prostate cancer. The mechanisms of carcinogenesis of DNA methylation include whole-genome hypomethylation, aberrant local hypermethylation of promoters and genomic instability. DNA methylation is closely related to the process of prostate cancer, as in DNA damage repair, hormone response, tumor cell invasion/metastasis, cell cycle regulation, and so on. Histone modification causes corresponding changes in chromosome structure and the level of gene transcription, and it may affect the cycle, differentiation and apoptosis of cells, resulting in prostate cancer. Some therapies have been developed targeting the epigenetic changes in prostate cancer, including DNA methyltransferases and histone deacetylase inhibitors, and have achieved certain desirable results.

  5. Theory of epigenetic coding.

    Science.gov (United States)

    Elder, D

    1984-06-07

    The logic of genetic control of development may be based on a binary epigenetic code. This paper revises the author's previous scheme dealing with the numerology of annelid metamerism in these terms. Certain features of the code had been deduced to be combinatorial, others not. This paradoxical contrast is resolved here by the interpretation that these features relate to different operations of the code; the combinatiorial to coding identity of units, the non-combinatorial to coding production of units. Consideration of a second paradox in the theory of epigenetic coding leads to a new solution which further provides a basis for epimorphic regeneration, and may in particular throw light on the "regeneration-duplication" phenomenon. A possible test of the model is also put forward.

  6. Epigenetics and brain evolution.

    Science.gov (United States)

    Keverne, Eric B

    2011-04-01

    Fundamental aspects of mammalian brain evolution occurred in the context of viviparity and placentation brought about by the epigenetic regulation of imprinted genes. Since the fetal placenta hormonally primes the maternal brain, two genomes in one individual are transgenerationally co-adapted to ensure maternal care and nurturing. Advanced aspects of neocortical brain evolution has shown very few genetic changes between monkeys and humans. Although these lineages diverged at approximately the same time as the rat and mouse (20 million years ago), synonymous sequence divergence between the rat and mouse is double that when comparing monkey with human sequences. Paradoxically, encephalization of rat and mouse are remarkably similar, while comparison of the human and monkey shows the human cortex to be three times the size of the monkey. This suggests an element of genetic stability between the brains of monkey and man with a greater emphasis on epigenetics providing adaptable variability.

  7. Epigenetics and Autism

    OpenAIRE

    Mbadiwe, Tafari; Millis, Richard M.

    2013-01-01

    This review identifies mechanisms for altering DNA-histone interactions of cell chromatin to upregulate or downregulate gene expression that could serve as epigenetic targets for therapeutic interventions in autism. DNA methyltransferases (DNMTs) can phosphorylate histone H3 at T6. Aided by protein kinase C ? 1, the DNMT lysine-specific demethylase-1 prevents demethylation of H3 at K4. During androgen-receptor-(AR-) dependent gene activation, this sequence may produce AR-dependent gene overac...

  8. [Epigenetics and obesity].

    Science.gov (United States)

    Casanello, Paola; Krause, Bernardo J; Castro-Rodríguez, José A; Uauy, Ricardo

    Current evidence supports the notion that exposure to various environmental conditions in early life may induce permanent changes in the epigenome that persist throughout the life-course. This article focuses on early changes associated with obesity in adult life. A review is presented on the factors that induce changes in whole genome (DNA) methylation in early life that are associated with adult onset obesity and related disorders. In contrast, reversal of epigenetic changes associated with weight loss in obese subjects has not been demonstrated. This contrasts with well-established associations found between obesity related DNA methylation patterns at birth and adult onset obesity and diabetes. Epigenetic markers may serve to screen indivuals at risk for obesity and assess the effects of interventions in early life that may delay or prevent obesity in early life. This might contribute to lower the obesity-related burden of death and disability at the population level. The available evidence indicates that epigenetic marks are in fact modifiable, based on modifications in the intrauterine environment and changes in food intake, physical activity and dietary patterns patterns during pregnancy and early years of adult life. This offers the opportunity to intervene before conception, during pregnancy, infancy, childhood, and also in later life. There must be documentation on the best preventive actions in terms of diet and physical activity that will modify or revert the adverse epigenetic markers, thus preventing obesity and diabetes in suceptible individuals and populations. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  9. Epigenetics and human obesity.

    Science.gov (United States)

    van Dijk, S J; Molloy, P L; Varinli, H; Morrison, J L; Muhlhausler, B S

    2015-01-01

    Recent technological advances in epigenome profiling have led to an increasing number of studies investigating the role of the epigenome in obesity. There is also evidence that environmental exposures during early life can induce persistent alterations in the epigenome, which may lead to an increased risk of obesity later in life. This paper provides a systematic review of studies investigating the association between obesity and either global, site-specific or genome-wide methylation of DNA. Studies on the impact of pre- and postnatal interventions on methylation and obesity are also reviewed. We discuss outstanding questions, and introduce EpiSCOPE, a multidisciplinary research program aimed at increasing the understanding of epigenetic changes in emergence of obesity. An electronic search for relevant articles, published between September 2008 and September 2013 was performed. From the 319 articles identified, 46 studies were included and reviewed. The studies provided no consistent evidence for a relationship between global methylation and obesity. The studies did identify multiple obesity-associated differentially methylated sites, mainly in blood cells. Extensive, but small, alterations in methylation at specific sites were observed in weight loss intervention studies, and several associations between methylation marks at birth and later life obesity were found. Overall, significant progress has been made in the field of epigenetics and obesity and the first potential epigenetic markers for obesity that could be detected at birth have been identified. Eventually this may help in predicting an individual's obesity risk at a young age and opens possibilities for introducing targeted prevention strategies. It has also become clear that several epigenetic marks are modifiable, by changing the exposure in utero, but also by lifestyle changes in adult life, which implies that there is the potential for interventions to be introduced in postnatal life to modify

  10. Epigenetics, Darwin, and Lamarck.

    Science.gov (United States)

    Penny, David

    2015-05-29

    It is not really helpful to consider modern environmental epigenetics as neo-Lamarckian; and there is no evidence that Lamarck considered the idea original to himself. We must all keep learning about inheritance, but attributing modern ideas to early researchers is not helpful, and can be misleading. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  11. Epigenetic priming of the metabolic syndrome.

    Science.gov (United States)

    Bruce, Kimberley D; Cagampang, Felino R

    2011-05-01

    The metabolic syndrome (MetS) represents a cluster of cardiometabolic risk factors, including central obesity, insulin resistance, glucose intolerance, dyslipidemia, hypertension, hyperinsulinemia and microalbuminuria, and more recently, nonalcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome (PCOS) and atherosclerosis. Although the concept of the MetS is subject to debate due to lack of a unifying underlying mechanism, the prevalence of a metabolic syndrome phenotype is rapidly increasing worldwide. Moreover, it is increasingly prevalent in children and adolescents of obese mothers. Evidence from both epidemiological and experimental animal studies now demonstrates that MetS onset is increasingly likely following exposure to suboptimal nutrition during critical periods of development, as observed in maternal obesity. Thus, the developmental priming of the MetS provides a common origin for this multifactorial disorder. Consequently, the mechanisms leading to this developmental priming have recently been the subject of intensive investigation. This review discusses recent data regarding the epigenetic modifications resulting from nutrition during early development that mediate persistent changes in the expression of key metabolic genes and contribute toward an adult metabolic syndrome phenotype. In addition, this review considers the role of the endogenous molecular circadian clock system, which has the potential to act at the interface between nutrient sensing and epigenetic processing. A continued and greater understanding of these mechanisms will eventually aid in the identification of individuals at high risk of cardiovascular disease (CVD) and type 2 diabetes, and help develop therapeutic interventions, in accordance with current global government strategy.

  12. Epigenetics of autism spectrum disorders.

    Science.gov (United States)

    Schanen, N Carolyn

    2006-10-15

    The autism spectrum disorders (ASD) comprise a complex group of behaviorally related disorders that are primarily genetic in origin. Involvement of epigenetic regulatory mechanisms in the pathogenesis of ASD has been suggested by the occurrence of ASD in patients with disorders arising from epigenetic mutations (fragile X syndrome) or that involve key epigenetic regulatory factors (Rett syndrome). Moreover, the most common recurrent cytogenetic abnormalities in ASD involve maternally derived duplications of the imprinted domain on chromosome 15q11-13. Thus, parent of origin effects on sharing and linkage to imprinted regions on chromosomes 15q and 7q suggest that these regions warrant specific examination from an epigenetic perspective, particularly because epigenetic modifications do not change the primary genomic sequence, allowing risk epialleles to evade detection using standard screening strategies. This review examines the potential role of epigenetic factors in the etiology of ASD.

  13. Epigenetics of Autism Spectrum Disorder.

    Science.gov (United States)

    Siu, Michelle T; Weksberg, Rosanna

    2017-01-01

    Autism spectrum disorder (ASD), one of the most common childhood neurodevelopmental disorders (NDDs), is diagnosed in 1 of every 68 children. ASD is incredibly heterogeneous both clinically and aetiologically. The etiopathogenesis of ASD is known to be complex, including genetic, environmental and epigenetic factors. Normal epigenetic marks modifiable by both genetics and environmental exposures can result in epigenetic alterations that disrupt the regulation of gene expression, negatively impacting biological pathways important for brain development. In this chapter we aim to summarize some of the important literature that supports a role for epigenetics in the underlying molecular mechanism of ASD. We provide evidence from work in genetics, from environmental exposures and finally from more recent studies aimed at directly determining ASD-specific epigenetic patterns, focusing mainly on DNA methylation (DNAm). Finally, we briefly discuss some of the implications of current research on potential epigenetic targets for therapeutics and novel avenues for future work.

  14. An emerging role for epigenetic factors in relation to executive function.

    Science.gov (United States)

    Ibrahim, Omar; Sutherland, Heidi G; Haupt, Larisa M; Griffiths, Lyn R

    2017-11-20

    Executive function (EF) includes a range of decision-making and higher-order thinking processes. Although the genetic basis of EF has been studied and reviewed, epigenetic factors that influence EF are an emerging field of interest; here, we summarize the current research. Work relating to different word combinations of 'Executive Function' and 'Epigenetic' was identified through three academic search directories. Inclusion criteria were human populations, EF testing, epigenetic testing or genotyping related to epigenetic regulation. To date, 14 studies have been reported, which examined epigenetic variation, in particular DNA methylation, in relation to EF assessments conducted in human subjects, with some positive associations found. Study populations included healthy cohorts, as well as psychiatric and neurological patient cohorts. Epigenetics in relation to EF is an emerging area of investigation with relatively few studies to date. Most assay DNA methylation, with some studies suggesting that epigenetic factors can be associated with EF. EF constitutes complex phenotypic and genotypic correlates that differ because of cohort attributes as well as the targeted task examined. Larger studies are required to further elucidate the contribution of epigenetic factors to EF with the identification of epigenetic modifications influencing EF having potential to provide new biomarkers for neuropsychiatric disorders. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

  15. Challenges in reporting on predetermined objectives to the Auditor-General: The case of Limpopo provincial departments

    OpenAIRE

    Melvin Diedericks

    2017-01-01

    Limpopo provincial departments like all other South African government departments are required to report on performance against predetermined objectives in terms of Section 40 of the Public Finance Management Act 1 of 1999, read in conjunction with Section 5.1.1 of the Treasury Regulations. The purpose of this article is to report on a study that was undertaken to establish the challenges faced by the Limpopo provincial departments in reporting on performance against predetermined objectives...

  16. Predetermining acceptable noise limits of EXAFS spectra in the limit of stochastic noise

    International Nuclear Information System (INIS)

    Hu, Yung-Jin; Booth, Corwin H

    2009-01-01

    The effect of stochastic noise on Extended X-ray Absorption Fine Structure (EXAFS) data measurement, analysis, and fitting is discussed. Stochastic noise reduces the ability to uniquely fit a calculated model to measured EXAFS data. Such noise can be reduced by common methods that increase the signal-to-noise ratio; however, these methods are not always practical. Therefore, predetermined, quantitative knowledge of the level of acceptable stochastic noise when fitting for a particular model system is essential in maximizing the chances of a successful EXAFS experiment and minimizing wasted beamtime. This paper outlines a method to estimate, through simulation, the acceptable level of stochastic noise in EXAFS spectra that still allows a successful test of a proposed model compound.

  17. Process for forming a nickel foil with controlled and predetermined permeability to hydrogen

    Science.gov (United States)

    Engelhaupt, Darell E.

    1981-09-22

    The present invention provides a novel process for forming a nickel foil having a controlled and predetermined hydrogen permeability. This process includes the steps of passing a nickel plating bath through a suitable cation exchange resin to provide a purified nickel plating bath free of copper and gold cations, immersing a nickel anode and a suitable cathode in the purified nickel plating bath containing a selected concentration of an organic sulfonic acid such as a napthalene-trisulfonic acid, electrodepositing a nickel layer having the thickness of a foil onto the cathode, and separating the nickel layer from the cathode to provide a nickel foil. The anode is a readily-corrodible nickel anode. The present invention also provides a novel nickel foil having a greater hydrogen permeability than palladium at room temperature.

  18. Process for forming a nickel foil with controlled and predetermined permeability to hydrogen

    International Nuclear Information System (INIS)

    Engelhaupt, D. E.

    1981-01-01

    The present invention provides a novel process for forming a nickel foil having a controlled and predetermined hydrogen permeability. This process includes the steps of passing a nickel plating bath through a suitable cation exchange resin to provide a purified nickel plating bath free of copper and gold cations, immersing a nickel anode and a suitable cathode in the purified nickel plating bath containing a selected concentration of an organic sulfonic acid such as a napthalene-trisulfonic acid, electrodepositing a nickel layer having the thickness of a foil onto the cathode, and separating the nickel layer from the cathode to provide a nickel foil. The anode is a readilycorrodible nickel anode. The present invention also provides a novel nickel foil having a greater hydrogen permeability than palladium at room temperature

  19. Epigenetics, obesity and early-life cadmium or lead exposure.

    Science.gov (United States)

    Park, Sarah S; Skaar, David A; Jirtle, Randy L; Hoyo, Cathrine

    2017-01-01

    Obesity is a complex and multifactorial disease, which likely comprises multiple subtypes. Emerging data have linked chemical exposures to obesity. As organismal response to environmental exposures includes altered gene expression, identifying the regulatory epigenetic changes involved would be key to understanding the path from exposure to phenotype and provide new tools for exposure detection and risk assessment. In this report, we summarize published data linking early-life exposure to the heavy metals, cadmium and lead, to obesity. We also discuss potential mechanisms, as well as the need for complete coverage in epigenetic screening to fully identify alterations. The keys to understanding how metal exposure contributes to obesity are improved assessment of exposure and comprehensive establishment of epigenetic profiles that may serve as markers for exposures.

  20. DNA Methylation: An Epigenetic Risk Factor in Preterm Birth

    Science.gov (United States)

    Menon, Ramkumar; Conneely, Karen N.; Smith, Alicia K.

    2012-01-01

    Spontaneous preterm birth (PTB; birth prior to 37 weeks of gestation) is a complex phenotype with multiple risk factors that complicate our understanding of its etiology. A number of recent studies have supported the hypothesis that epigenetic modifications such as DNA methylation induced by pregnancy-related risk factors may influence the risk of PTB or result in changes that predispose a neonate to adult-onset diseases. The critical role of timing of gene expression in the etiology of PTB makes it a highly relevant disorder in which to examine the potential role of epigenetic changes. Because changes in DNA methylation patterns can result in long-term consequences, it is of critical interest to identify the epigenetic patterns associated with adverse pregnancy outcomes. This review examines the potential role of DNA methylation as a risk factor for PTB and discusses several issues and limitations that should be considered when planning DNA methylation studies. PMID:22228737

  1. Epstein-Barr virus: a master epigenetic manipulator.

    Science.gov (United States)

    Scott, Rona S

    2017-10-01

    Like all herpesviruses, the ability of Epstein-Barr virus (EBV) to establish life-long persistent infections is related to a biphasic viral lifecycle that involves latency and reactivation/lytic replication. Memory B cells serve as the EBV latency compartment where silencing of viral gene expression allows maintenance of the viral genome, avoidance of immune surveillance, and life-long carriage. Upon viral reactivation, viral gene expression is induced for replication, progeny virion production, and viral spread. EBV uses the host epigenetic machinery to regulate its distinct viral gene expression states. However, epigenetic manipulation by EBV affects the host epigenome by reprogramming cells in ways that leave long-lasting, oncogenic phenotypes. Such virally-induced epigenetic alterations are evident in EBV-associated cancers. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Developmental plasticity and epigenetic mechanisms underpinning metabolic and cardiovascular diseases.

    Science.gov (United States)

    Low, Felicia M; Gluckman, Peter D; Hanson, Mark A

    2011-06-01

    The importance of developmental factors in influencing the risk of later-life disease has a strong evidence base derived from multiple epidemiological, clinical and experimental studies in animals and humans. During early life, an organism is able to adjust its phenotypic development in response to environmental cues. Such developmentally plastic responses evolved as a fitness-maximizing strategy to cope with variable environments. There are now increasing data that these responses are, at least partially, underpinned by epigenetic mechanisms. A mismatch between the early and later-life environments may lead to inappropriate early life-course epigenomic changes that manifest in later life as increased vulnerability to disease. There is also growing evidence for the transgenerational transmission of epigenetic marks. This article reviews the evidence that susceptibility to metabolic and cardiovascular disease in humans is linked to changes in epigenetic marks induced by early-life environmental cues, and discusses the clinical, public health and therapeutic implications that arise.

  3. Combining genomic and proteomic approaches for epigenetics research

    Science.gov (United States)

    Han, Yumiao; Garcia, Benjamin A

    2014-01-01

    Epigenetics is the study of changes in gene expression or cellular phenotype that do not change the DNA sequence. In this review, current methods, both genomic and proteomic, associated with epigenetics research are discussed. Among them, chromatin immunoprecipitation (ChIP) followed by sequencing and other ChIP-based techniques are powerful techniques for genome-wide profiling of DNA-binding proteins, histone post-translational modifications or nucleosome positions. However, mass spectrometry-based proteomics is increasingly being used in functional biological studies and has proved to be an indispensable tool to characterize histone modifications, as well as DNA–protein and protein–protein interactions. With the development of genomic and proteomic approaches, combination of ChIP and mass spectrometry has the potential to expand our knowledge of epigenetics research to a higher level. PMID:23895656

  4. Epigenetics in women's health care.

    Science.gov (United States)

    Pozharny, Yevgeniya; Lambertini, Luca; Clunie, Garfield; Ferrara, Lauren; Lee, Men-Jean

    2010-01-01

    Epigenetics refers to structural modifications to genes that do not change the nucleotide sequence itself but instead control and regulate gene expression. DNA methylation, histone modification, and RNA regulation are some of the mechanisms involved in epigenetic modification. Epigenetic changes are believed to be a result of changes in an organism's environment that result in fixed and permanent changes in most differentiated cells. Some environmental changes that have been linked to epigenetic changes include starvation, folic acid, and various chemical exposures. There are periods in an organism's life cycle in which the organism is particularly susceptible to epigenetic influences; these include fertilization, gametogenesis, and early embryo development. These are also windows of opportunity for interventions during the reproductive life cycle of women to improve maternal-child health. New data suggest that epigenetic influences might be involved in the regulation of fetal development and the pathophysiology of adult diseases such as cancer, diabetes, obesity, and neurodevelopmental disorders. Various epigenetic mechanisms may also be involved in the pathogenesis of preeclampsia and intrauterine growth restriction. Additionally, environmental exposures are being held responsible for causing epigenetic changes that lead to a disease process. Exposure to heavy metals, bioflavonoids, and endocrine disruptors, such as bisphenol A and phthalates, has been shown to affect the epigenetic memory of an organism. Their long-term effects are unclear at this point, but many ongoing studies are attempting to elucidate the pathophysiological effects of such gene-environment interactions. (c) 2010 Mount Sinai School of Medicine.

  5. The Key Role of Epigenetics in the Persistence of Asexual Lineages

    Directory of Open Access Journals (Sweden)

    Emilie Castonguay

    2012-01-01

    Full Text Available Asexual organisms, often perceived as evolutionary dead ends, can be long-lived and geographically widespread. We propose that epigenetic mechanisms could play a crucial role in the evolutionary persistence of these lineages. Genetically identical organisms could rely on phenotypic plasticity to face environmental variation. Epigenetic modifications could be the molecular mechanism enabling such phenotypic plasticity; they can be influenced by the environment and act at shorter timescales than mutation. Recent work on the asexual vertebrate Chrosomus eos-neogaeus (Pisces: Cyprinidae provides broad insights into the contribution of epigenetics in genetically identical individuals. We discuss the extension of these results to other asexual organisms, in particular those resulting from interspecific hybridizations. We finally develop on the evolutionary relevance of epigenetic variation in the context of heritability.

  6. General-Purpose Genotype or How Epigenetics Extend the Flexibility of a Genotype

    Directory of Open Access Journals (Sweden)

    Rachel Massicotte

    2012-01-01

    Full Text Available This project aims at investigating the link between individual epigenetic variability (not related to genetic variability and the variation of natural environmental conditions. We studied DNA methylation polymorphisms of individuals belonging to a single genetic lineage of the clonal diploid fish Chrosomus eos-neogaeus sampled in seven geographically distant lakes. In spite of a low number of informative fragments obtained from an MSAP analysis, individuals of a given lake are epigenetically similar, and methylation profiles allow the clustering of individuals in two distinct groups of populations among lakes. More importantly, we observed a significant pH variation that is consistent with the two epigenetic groups. It thus seems that the genotype studied has the potential to respond differentially via epigenetic modifications under variable environmental conditions, making epigenetic processes a relevant molecular mechanism contributing to phenotypic plasticity over variable environments in accordance with the GPG model.

  7. Comparative epigenetics: relevance to the regulation of production and health traits in cattle.

    Science.gov (United States)

    Doherty, Rachael; O' Farrelly, Cliona; Meade, Kieran G

    2014-08-01

    With the development of genomic, transcriptomic and bioinformatic tools, recent advances in molecular technologies have significantly impacted bovine bioscience research and are revolutionising animal selection and breeding. Integration of epigenetic information represents yet another challenging molecular frontier. Epigenetics is the study of biochemical modifications to DNA and to histones, the proteins that provide stability to DNA. These epigenetic changes are induced by environmental stimuli; they alter gene expression and are potentially heritable. Epigenetics research holds the key to understanding how environmental factors contribute to phenotypic variation in traits of economic importance in cattle including development, nutrition, behaviour and health. In this review, we discuss the potential applications of epigenetics in bovine research, using breakthroughs in human and murine research to signpost the way. © 2014 Stichting International Foundation for Animal Genetics.

  8. Epigenetics primer: why the clinician should care about epigenetics.

    Science.gov (United States)

    Duarte, Julio D

    2013-12-01

    Epigenetics describes heritable alterations of gene expression that do not involve DNA sequence variation and are changeable throughout an organism's lifetime. Not only can epigenetic status influence drug response, but it can also be modulated by drugs. In this review, the three major epigenetic mechanisms are described: covalent DNA modification, histone protein modification, and regulation by noncoding RNA. Further, this review describes how drug therapy can influence, and be influenced by, these mechanisms. Drugs with epigenetic mechanisms are already in use, with many more likely to be approved within the next few years. As the understanding of epigenetic processes improves, so will the ability to use these data in the clinic to improve patient care. © 2013 Pharmacotherapy Publications, Inc.

  9. Epigenetic therapy in myeloproliferative neoplasms: evidence and perspectives

    Science.gov (United States)

    Vannucchi, Alessandro M; Guglielmelli, Paola; Rambaldi, Alessandro; Bogani, Costanza; Barbui, Tiziano

    2009-01-01

    The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), which include polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, originate from a stem cell-derived clonal myeloproliferation that manifests itself with variable haematopoietic cell lineage involvement; they are characterized by a high degree of similarities and the chance to transform each to the other and to evolve into acute leukaemia. Their molecular pathogenesis has been associated with recurrent acquired mutations in janus kinase 2 (JAK2) and myeloproliferative leukemia virus oncogene (MPL). These discoveries have simplified the diagnostic approach and provided a number of clues to understanding the phenotypic expression of MPNs; furthermore, they represented a framework for developing and/or testing in clinical trials small molecules acting as tyrosine kinase inhibitors. On the other hand, evidence of abnormal epigenetic gene regulation as a mechanism potentially contributing to the pathogenesis and the phenotypic diversity of MPNs is still scanty; however, study of epigenetics in MPNs represents an active field of research. The first clinical trials with epigenetic drugs have been completed recently, whereas others are still ongoing; results have been variable and at present do not allow any firm conclusion. Novel basic and translational information concerning epigenetic gene regulation in MPNs and the perspectives for therapy will be critically addressed in this review. PMID:19522842

  10. Epigenetic reprogramming in mammalian species after SCNT-based cloning.

    Science.gov (United States)

    Niemann, Heiner

    2016-07-01

    The birth of "Dolly," the first mammal cloned from an adult mammary epithelial cell, abolished the decades-old scientific dogma implying that a terminally differentiated cell cannot be reprogrammed into a pluripotent embryonic state. The most dramatic epigenetic reprogramming occurs in SCNT when the expression profile of a differentiated cell is abolished and a new embryo-specific expression profile, involving 10,000 to 12,000 genes, and thus, most genes of the entire genome is established, which drives embryonic and fetal development. The initial release from somatic cell epigenetic constraints is followed by establishment of post-zygotic expression patterns, X-chromosome inactivation, and adjustment of telomere length. Somatic cell nuclear transfer may be associated with a variety of pathologic changes of the fetal and placental phenotype in a proportion of cloned offspring, specifically in ruminants, that are thought to be caused by aberrant epigenetic reprogramming. Improvements in our understanding of this dramatic epigenetic reprogramming event will be instrumental in realizing the great potential of SCNT for basic research and for important agricultural and biomedical applications. Here, current knowledge on epigenetic reprogramming after use of SCNT in livestock is reviewed, with emphasis on gene-specific and global DNA methylation, imprinting, X-chromosome inactivation, and telomere length restoration in early development. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. An epigenetic biomarker of aging for lifespan and healthspan

    Science.gov (United States)

    Levine, Morgan E.; Lu, Ake T.; Quach, Austin; Chen, Brian H.; Assimes, Themistocles L.; Bandinelli, Stefania; Hou, Lifang; Baccarelli, Andrea A.; Stewart, James D.; Li, Yun; Whitsel, Eric A.; Wilson, James G; Reiner, Alex P; Aviv, Abraham; Lohman, Kurt; Liu, Yongmei; Ferrucci, Luigi

    2018-01-01

    Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging. PMID:29676998

  12. Epigenetics of kidney disease.

    Science.gov (United States)

    Wanner, Nicola; Bechtel-Walz, Wibke

    2017-07-01

    DNA methylation and histone modifications determine renal programming and the development and progression of renal disease. The identification of the way in which the renal cell epigenome is altered by environmental modifiers driving the onset and progression of renal diseases has extended our understanding of the pathophysiology of kidney disease progression. In this review, we focus on current knowledge concerning the implications of epigenetic modifications during renal disease from early development to chronic kidney disease progression including renal fibrosis, diabetic nephropathy and the translational potential of identifying new biomarkers and treatments for the prevention and therapy of chronic kidney disease and end-stage kidney disease.

  13. Epigenetic inheritance in apomictic dandelions

    NARCIS (Netherlands)

    Preite, V.

    2016-01-01

    Epigenetic variation, such as changes in DNA methylations, regulatory small RNAs (sRNAs) and chromatin modifications can be induced by environmental stress. There is increasing information that such induced epigenetic modifications can be transmitted to offspring, potentially mediating adaptive

  14. Epigenetic Alterations in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Johannes eGräff

    2015-12-01

    Full Text Available Alzheimer’s disease (AD is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD.

  15. Epigenetic Mechanisms Underlie Genome Development

    Science.gov (United States)

    Lamm, Ehud

    2013-01-01

    Technological and methodological advances, in particular next-generation sequencing and chromatin profiling, has led to a deluge of data on epigenetic mechanisms and processes. Epigenetic regulation in the brain is no exception. In this commentary, Ehud Lamm writes that extending existing frameworks for thinking about psychological development to…

  16. Epigenetic inheritance, prions and evolution

    Indian Academy of Sciences (India)

    The field of epigenetics has grown explosively in the past two decades or so. As currently defined, epigenetics deals with heritable, metastable and usually reversible changes that do not involve alterations in DNA sequence, but alter the way that information encoded inDNAis utilized.The bulk of current research in ...

  17. Evolutionary significance of epigenetic variation

    NARCIS (Netherlands)

    Richards, C.L.; Verhoeven, K.J.F.; Bossdorf, O.; Wendel, J.F.; Greilhuber, J.; Dolezel, J.; Leitch, I.J.

    2012-01-01

    Several chapters in this volume demonstrate how epigenetic work at the molecular level over the last few decades has revolutionized our understanding of genome function and developmental biology. However, epigenetic processes not only further our understanding of variation and regulation at the

  18. Epigenetic Alterations in Alzheimer's Disease.

    Science.gov (United States)

    Sanchez-Mut, Jose V; Gräff, Johannes

    2015-01-01

    Alzheimer's disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD.

  19. Is Glioblastoma an Epigenetic Malignancy?

    International Nuclear Information System (INIS)

    Maleszewska, Marta; Kaminska, Bozena

    2013-01-01

    Epigenetic modifications control gene expression by regulating the access of nuclear proteins to their target DNA and have been implicated in both normal cell differentiation and oncogenic transformation. Epigenetic abnormalities can occur both as a cause and as a consequence of cancer. Oncogenic transformation can deeply alter the epigenetic information enclosed in the pattern of DNA methylation or histone modifications. In addition, in some cancers epigenetic dysfunctions can drive oncogenic transformation. Growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer, i.e., mutations in the metabolic enzymes SDH, FH, and IDH may contribute to cancer development. Epigenetic-based mechanisms are reversible and the possibility of “resetting” the abnormal cancer epigenome by applying pharmacological or genetic strategies is an attractive, novel approach. Gliomas are incurable with all current therapeutic approaches and new strategies are urgently needed. Increasing evidence suggests the role of epigenetic events in development and/or progression of gliomas. In this review, we summarize current data on the occurrence and significance of mutations in the epigenetic and metabolic enzymes in pathobiology of gliomas. We discuss emerging therapies targeting specific epigenetic modifications or chromatin modifying enzymes either alone or in combination with other treatment regimens

  20. Epigenetics and autism.

    Science.gov (United States)

    Mbadiwe, Tafari; Millis, Richard M

    2013-01-01

    This review identifies mechanisms for altering DNA-histone interactions of cell chromatin to upregulate or downregulate gene expression that could serve as epigenetic targets for therapeutic interventions in autism. DNA methyltransferases (DNMTs) can phosphorylate histone H3 at T6. Aided by protein kinase C β 1, the DNMT lysine-specific demethylase-1 prevents demethylation of H3 at K4. During androgen-receptor-(AR-) dependent gene activation, this sequence may produce AR-dependent gene overactivation which may partly explain the male predominance of autism. AR-dependent gene overactivation in conjunction with a DNMT mechanism for methylating oxytocin receptors could produce high arousal inputs to the amygdala resulting in aberrant socialization, a prime characteristic of autism. Dysregulation of histone methyltransferases and histone deacetylases (HDACs) associated with low activity of methyl CpG binding protein-2 at cytosine-guanine sites in genes may reduce the capacity for condensing chromatin and silencing genes in frontal cortex, a site characterized by decreased cortical interconnectivity in autistic subjects. HDAC1 inhibition can overactivate mRNA transcription, a putative mechanism for the increased number of cerebral cortical columns and local frontal cortex hyperactivity in autistic individuals. These epigenetic mechanisms underlying male predominance, aberrant social interaction, and low functioning frontal cortex may be novel targets for autism prevention and treatment strategies.

  1. Epigenetics and Autism

    Directory of Open Access Journals (Sweden)

    Tafari Mbadiwe

    2013-01-01

    Full Text Available This review identifies mechanisms for altering DNA-histone interactions of cell chromatin to upregulate or downregulate gene expression that could serve as epigenetic targets for therapeutic interventions in autism. DNA methyltransferases (DNMTs can phosphorylate histone H3 at T6. Aided by protein kinase Cβ1, the DNMT lysine-specific demethylase-1 prevents demethylation of H3 at K4. During androgen-receptor-(AR- dependent gene activation, this sequence may produce AR-dependent gene overactivation which may partly explain the male predominance of autism. AR-dependent gene overactivation in conjunction with a DNMT mechanism for methylating oxytocin receptors could produce high arousal inputs to the amygdala resulting in aberrant socialization, a prime characteristic of autism. Dysregulation of histone methyltransferases and histone deacetylases (HDACs associated with low activity of methyl CpG binding protein-2 at cytosine-guanine sites in genes may reduce the capacity for condensing chromatin and silencing genes in frontal cortex, a site characterized by decreased cortical interconnectivity in autistic subjects. HDAC1 inhibition can overactivate mRNA transcription, a putative mechanism for the increased number of cerebral cortical columns and local frontal cortex hyperactivity in autistic individuals. These epigenetic mechanisms underlying male predominance, aberrant social interaction, and low functioning frontal cortex may be novel targets for autism prevention and treatment strategies.

  2. Stress, Epigenetics, and Alcoholism

    Science.gov (United States)

    Moonat, Sachin; Pandey, Subhash C.

    2012-01-01

    Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders. Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker’s dysphoria. One molecule that may help mediate the relationship between stress and alcohol consumption is brain-derived neurotrophic factor (BDNF), a protein that regulates the structure and function of the sites where two nerve cells interact and exchange nerve signals (i.e., synapses) and which is involved in numerous physiological processes. Aberrant regulation of BDNF signaling and alterations in synapse activity (i.e., synaptic plasticity) have been associated with the pathophysiology of stress-related disorders and alcoholism. Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity—for example, by modifying the structure of the DNA–protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes. Studies regarding the epigenetic control of BDNF signaling and synaptic plasticity provide a promising direction to understand the mechanisms mediating the interaction between stress and alcoholism. PMID:23584115

  3. Analysis of the predetermining effect of a sex realizer by ovary transplantations in the monogenic flyChrysomya rufifacies.

    Science.gov (United States)

    Ullerich, Fritz-Helmut

    1980-02-01

    In the heterozygousF'/f female-producing females of the strictly monogenic blowflyChrysomya rufifacies the gene product of the dominant or epistatic female sex realizerF' which causes sexpredetermination is thought to be synthesized either by cells of the germ line (oocytes, nurse cells or oogonia) or by somatic cells and then transferred into the oocytes. To determine the possible site of synthesis, reciprocal transplantations were made of prepupal ovaries between female-producing (thelygenic; t) and male-producing (arrhenogenic; a) females ofChrysomya rufifacies. In another series of experiments prepupal host females of the wild t-type and a-type were each provided with one additional ovary either from a0type (f/f) or a t-type (F'/f) prepupa (neither were distinguishable by their phenotypes). In all these experiments the donor females were marked by the recessive sex-linked mutation 'white' (w/w); white eyes, white Malpighian tubules). In a considerable number of cases the implanted ovaries were in contact with the host's own oviduct and grew normally, but the rate of hatched adults was somewhat reduced. Crosses between such host females andw/w males (f/f) produced female or male offspring with white eyes from the eggs of the implantedw/w ovary, as well as flies with wild-type eyes (+/w) which had developed in the host's own ovaries. In all cases so far examined, the genetically thelygenic (or arrhenogenic) host females with an additional ovary implanted from an arrhenogenic (thelygenic) donor, produced progeny of both sexes: sons (daughters) from the eggs of the donor's ovary and daugthers (sons) from the eggs of the host's own gonads.These results demonstrate that the ovaries of the t-females ofChrysomya rufifacies at least from the early prepupal stage, are autonomous for the product of theF' gene. Transplantations of the premordial germ cells (pole cells) are planned to find out whether the predeterminingF' gene product is synthesized before the prepupal

  4. Epigenetic regulation of normal human mammary cell type-specific miRNAs

    Energy Technology Data Exchange (ETDEWEB)

    Vrba, Lukas [Univ. of Arizona, Tucson, AZ (United States). Arizona Cancer Center; Inst. of Plant Molecular Biology, Ceske Budejovice (Czech Republic). Biology Centre ASCR; Garbe, James C. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Center; Stampfer, Martha R. [Univ. of Arizona, Tucson, AZ (United States). Arizona Cancer Center; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Center; Futscher, Bernard W. [Univ. of Arizona, Tucson, AZ (United States). Arizona Cancer Center and Dept. of Pharmacology & Toxicology

    2011-08-26

    Epigenetic mechanisms are important regulators of cell type–specific genes, including miRNAs. In order to identify cell type-specific miRNAs regulated by epigenetic mechanisms, we undertook a global analysis of miRNA expression and epigenetic states in three isogenic pairs of human mammary epithelial cells (HMEC) and human mammary fibroblasts (HMF), which represent two differentiated cell types typically present within a given organ, each with a distinct phenotype and a distinct epigenotype. While miRNA expression and epigenetic states showed strong interindividual concordance within a given cell type, almost 10% of the expressed miRNA showed a cell type–specific pattern of expression that was linked to the epigenetic state of their promoter. The tissue-specific miRNA genes were epigenetically repressed in nonexpressing cells by DNA methylation (38%) and H3K27me3 (58%), with only a small set of miRNAs (21%) showing a dual epigenetic repression where both DNA methylation and H3K27me3 were present at their promoters, such as MIR10A and MIR10B. Individual miRNA clusters of closely related miRNA gene families can each display cell type–specific repression by the same or complementary epigenetic mechanisms, such as the MIR200 family, and MIR205, where fibroblasts repress MIR200C/141 by DNA methylation, MIR200A/200B/429 by H3K27me3, and MIR205 by both DNA methylation and H3K27me3. Since deregulation of many of the epigenetically regulated miRNAs that we identified have been linked to disease processes such as cancer, it is predicted that compromise of the epigenetic control mechanisms is important for this process. Overall, these results highlight the importance of epigenetic regulation in the control of normal cell type–specific miRNA expression.

  5. Molecular epigenetics in the management of ovarian cancer: Are we investigating a rational clinical promise?

    Directory of Open Access Journals (Sweden)

    Ha eNguyen

    2014-04-01

    Full Text Available Epigenetics is essentially a phenotypical change in gene expression without any alteration of the DNA sequence; the emergence of epigenetics in cancer research and mainstream oncology is fueling new hope. However, it is not yet known whether this knowledge will translate to improved clinical management of ovarian cancer. In this malignancy, women are still undergoing chemotherapy similar to what was approved in 1978, which to this day represents one of the biggest breakthroughs for treating ovarian cancer. While liquid tumors are benefitting from epigenetically-related therapies, solid tumors like ovarian cancer are not (yet?. Herein we will review the science of molecular epigenetics, especially DNA methylation, histone modifications and microRNA, but also include transcription factors since they, too, are important in ovarian cancer. Preclinical and clinical research on the role of epigenetic modifications is summarized as well. Sadly, ovarian cancer remains an idiopathic disease, for the most part, and there are many areas of patient management which could benefit from improved technology. This review will also highlight the evidence suggesting that epigenetics may have preclinical utility in pharmacology and clinical applications for prognosis and diagnosis. Lastly, drugs currently in clinical trials (i.e. histone deacetylase inhibitors are discussed along with the promise for epigenetics in the exploitation of chemoresistance. Whether epigenetics will ultimately be the answer to better management in ovarian cancer is currently unknown; what we have now is hope.

  6. The political implications of epigenetics.

    Science.gov (United States)

    Robison, Shea K

    2016-01-01

    Epigenetics, which is just beginning to attract public attention and policy discussion, challenges conventional understanding of gene-environment interaction and intergenerational inheritance and perhaps much more besides. Does epigenetics challenge modern political ideologies? I analyzed the narratives of obesity and epigenetics recently published in the more liberal New York Times and the more conservative Wall Street Journal. For the years 2010 through 2014, 50 articles on obesity and 29 articles on epigenetics were identified, and elements in their causal narratives were quantitatively analyzed using a well described narrative policy framework. The narratives on obesity aligned with the two newspapers' reputed ideologies. However, the narratives on epigenetics aligned with neither ideology but freely mixed liberal and conservative elements. This small study may serve as a starting point for broader studies of epigenetics as it comes to affect political ideologies and, in turn, public policies. The narrative mix reported here could yet prove vulnerable to ideological capture, or, more optimistically, could portend the emergence of a "third-way" narrative using epigenetics to question atomistic individualism and allowing for less divisiveness in public-health domains such as obesity.

  7. Evolution, epigenetics and cooperation.

    Science.gov (United States)

    Bateson, Patrick

    2014-04-01

    Explanations for biological evolution in terms of changes in gene frequencies refer to outcomes rather than process. Integrating epigenetic studies with older evolutionary theories has drawn attention to the ways in which evolution occurs. Adaptation at the level of the gene is givingway to adaptation at the level of the organism and higher-order assemblages of organisms. These ideas impact on the theories of how cooperation might have evolved. Two of the theories, i.e. that cooperating individuals are genetically related or that they cooperate for self-interested reasons, have been accepted for a long time. The idea that adaptation takes place at the level of groups is much more controversial. However, bringing together studies of development with those of evolution is taking away much of the heat in the debate about the evolution of group behaviour.

  8. [Schizophrenia, environment and epigenetics].

    Science.gov (United States)

    Must, Anita; Janka, Zoltan; Horvath, Szatmar

    2011-12-01

    Psychotic, cognitive and affective symptoms defining schizophrenia may, though much less severe, manifest themselves in up to 10 to 20% of the general population. What explains the fact that in certain cases the symptoms require even constant medical supervision, while others are capable of living a normal life within social conventions? Which factors lead to the transition of mild, subclinical manifestations and vulnerability indicators towards the outburst of one of the most severe and depriving mental disorders? Genetic susceptibility is undoubtedly crucial. More recent research findings emphasize the modifying effect of specific environmental factors on gene expression. The gene-environment interplay may induce so-called epigenetic alterations which may manifest themselves over several generations. Future integrative, multi-dimensional and flexible schizophrenia research approaches focusing on the identification of neurobiological and cognitive outcomes are much needed to understand disease vulnerability, susceptibility mechanisms, periods and interactions. Research methods may differ, but our aim is common - establishing more effective diagnostic and therapeutic interventions.

  9. Obesity and diabetes: from genetics to epigenetics.

    Science.gov (United States)

    Burgio, Ernesto; Lopomo, Angela; Migliore, Lucia

    2015-04-01

    Obesity is becoming an epidemic health problem. During the last years not only genetic but also, and primarily, environmental factors have been supposed to contribute to the susceptibility to weight gain or to develop complications such as type 2 diabetes. In spite of the intense efforts to identify genetic predisposing variants, progress has been slow and success limited, and the common obesity susceptibility variants identified only explains a small part of the individual variation in risk. Moreover, there is evidence that the current epidemic of obesity and diabetes is environment-driven. Recent studies indicate that normal metabolic regulation during adulthood besides requiring a good balance between energy intake and energy expenditure, can be also affected by pre- and post-natal environments. In fact, maternal nutritional constraint during pregnancy can alter the metabolic phenotype of the offspring by means of epigenetic regulation of specific genes, and this can be passed to the next generations. Studies focused on epigenetic marks in obesity found altered methylation and/or histone acetylation levels in genes involved in specific but also in more general metabolic processes. Recent researches point out the continuous increase of "obesogens", in the environment and food chains, above all endocrine disruptors, chemicals that interfere with many homeostatic mechanisms. Taken into account the already existing data on the effects of obesogens, and the multiple potential targets with which they might interfere daily, it seems likely that the exposure to obesogens can have an important role in the obesity and diabesity pandemic.

  10. Epigenetic Silencing of DKK3 in Medulloblastoma

    Directory of Open Access Journals (Sweden)

    André Oberthuer

    2013-04-01

    Full Text Available Medulloblastoma (MB is a malignant pediatric brain tumor arising in the cerebellum consisting of four distinct subgroups: WNT, SHH, Group 3 and Group 4, which exhibit different molecular phenotypes. We studied the expression of Dickkopf (DKK 1–4 family genes, inhibitors of the Wnt signaling cascade, in MB by screening 355 expression profiles derived from four independent datasets. Upregulation of DKK1, DKK2 and DKK4 mRNA was observed in the WNT subgroup, whereas DKK3 was downregulated in 80% MBs across subgroups with respect to the normal cerebellum (p < 0.001. Since copy number aberrations targeting the DKK3 locus (11p15.3 are rare events, we hypothesized that epigenetic factors could play a role in DKK3 regulation. Accordingly, we studied 77 miRNAs predicting to repress DKK3; however, no significant inverse correlation between miRNA/mRNA expression was observed. Moreover, the low methylation levels in the DKK3 promoters (median: 3%, 5% and 5% for promoter 1, 2 and 3, respectively excluded the downregulation of gene expression by methylation. On the other hand, the treatment of MB cells with Trichostatin A (TSA, a potent inhibitor of histone deacetylases (HDAC, was able to restore both DKK3 mRNA and protein. In conclusion, DKK3 downregulation across all MB subgroups may be due to epigenetic mechanisms, in particular, through chromatin condensation.

  11. [Nutritional epigenetics and epigenetic effects of human breast milk].

    Science.gov (United States)

    Lukoyanova, O L; Borovik, T E

    The article provides an overview of the current literature on nutritional epigenetics. There are currently actively studied hypothesis that nutrition especially in early life or in critical periods of the development, may have a role in modulating gene expression, and, therefore, have later effects on health in adults. Nutritional epigenetics concerns knowledge about the possible effects of nutrients on gene expression. Human breast milk is well-known for its ability in preventing necrotizing enterocolitis, infectious diseases, and also non-communicable diseases, such as obesity and related disorders. This paper discusses about presumed epigenetic effects of human breast milk and some its components. While evidence suggests that a direct relationship may exist of some components of human breast milk with epigenetic changes, the mechanisms involved are stillunclear.

  12. Epigenetics and Evolution: Transposons and the Stochastic Epigenetic Modification Model

    Directory of Open Access Journals (Sweden)

    Sergio Branciamore

    2015-04-01

    Full Text Available In addition to genetic variation, epigenetic variation and transposons can greatly affect the evolutionary fitnesses landscape and gene expression. Previously we proposed a mathematical treatment of a general epigenetic variation model that we called Stochastic Epigenetic Modification (SEM model. In this study we follow up with a special case, the Transposon Silencing Model (TSM, with, once again, emphasis on quantitative treatment. We have investigated the evolutionary effects of epigenetic changes due to transposon (T insertions; in particular, we have considered a typical gene locus A and postulated that (i the expression level of gene A depends on the epigenetic state (active or inactive of a cis- located transposon element T, (ii stochastic variability in the epigenetic silencing of T occurs only in a short window of opportunity during development, (iii the epigenetic state is then stable during further development, and (iv the epigenetic memory is fully reset at each generation. We develop the model using two complementary approaches: a standard analytical population genetics framework (di usion equations and Monte-Carlo simulations. Both approaches led to similar estimates for the probability of fixation and time of fixation of locus TA with initial frequency P in a randomly mating diploid population of effective size Ne. We have ascertained the e ect that ρ, the probability of transposon Modification during the developmental window, has on the population (species. One of our principal conclusions is that as ρ increases, the pattern of fixation of the combined TA locus goes from "neutral" to "dominant" to "over-dominant". We observe that, under realistic values of ρ, epigenetic Modifications can provide an e cient mechanism for more rapid fixation of transposons and cis-located gene alleles. The results obtained suggest that epigenetic silencing, even if strictly transient (being reset at each generation, can still have signi cant

  13. Epigenetic Transgenerational Actions of Vinclozolin on the Development of Disease and Cancer

    Science.gov (United States)

    Skinner, Michael K.; Anway, Matthew D.

    2018-01-01

    Exposure to an environmental endocrine disruptor (e.g., vinclozolin) during embryonic gonadal sex determination appears to alter the male germ line epigenome and subsequently promotes transgenerational adult onset disease. The epigenetic mechanism involves the induction of new imprinted-like genes/DNA sequences in the germ line that appear to transmit disease phenotypes. The disease phenotypes include testis abnormalities, prostate disease, kidney disease, immune abnormalities, and tumor development. This epigenetic transgenerational disease mechanism provides a unique perspective from which to view inheritable adult onset disease states, such as cancer, and ultimately offers new insights into novel diagnostic and therapeutic strategies. PMID:17956218

  14. Epigenetic Regulation of Telomere Maintenance

    Czech Academy of Sciences Publication Activity Database

    Fojtová, M.; Fajkus, Jiří

    2014-01-01

    Roč. 143, 1-3 (2014), s. 125-135 ISSN 1424-8581 Institutional support: RVO:68081707 Keywords : Chromatin * DNA methylation * Epigenetic s Subject RIV: BO - Biophysics Impact factor: 1.561, year: 2014

  15. The epigenetic landscape of alcoholism.

    Science.gov (United States)

    Krishnan, Harish R; Sakharkar, Amul J; Teppen, Tara L; Berkel, Tiffani D M; Pandey, Subhash C

    2014-01-01

    Alcoholism is a complex psychiatric disorder that has a multifactorial etiology. Epigenetic mechanisms are uniquely capable of accounting for the multifactorial nature of the disease in that they are highly stable and are affected by environmental factors, including alcohol itself. Chromatin remodeling causes changes in gene expression in specific brain regions contributing to the endophenotypes of alcoholism such as tolerance and dependence. The epigenetic mechanisms that regulate changes in gene expression observed in addictive behaviors respond not only to alcohol exposure but also to comorbid psychopathology such as the presence of anxiety and stress. This review summarizes recent developments in epigenetic research that may play a role in alcoholism. We propose that pharmacologically manipulating epigenetic targets, as demonstrated in various preclinical models, hold great therapeutic potential in the treatment and prevention of alcoholism. © 2014 Elsevier Inc. All rights reserved.

  16. Epigenetic Modifications and Diabetic Retinopathy

    Directory of Open Access Journals (Sweden)

    Renu A. Kowluru

    2013-01-01

    Full Text Available Diabetic retinopathy remains one of the most debilitating chronic complications, but despite extensive research in the field, the exact mechanism(s responsible for how retina is damaged in diabetes remains ambiguous. Many metabolic pathways have been implicated in its development, and genes associated with these pathways are altered. Diabetic environment also facilitates epigenetics modifications, which can alter the gene expression without permanent changes in DNA sequence. The role of epigenetics in diabetic retinopathy is now an emerging area, and recent work has shown that genes encoding mitochondrial superoxide dismutase (Sod2 and matrix metalloproteinase-9 (MMP-9 are epigenetically modified, activates of epigenetic modification enzymes, histone lysine demethylase 1 (LSD1, and DNA methyltransferase are increased, and the micro RNAs responsible for regulating nuclear transcriptional factor and VEGF are upregulated. With the growing evidence of epigenetic modifications in diabetic retinopathy, better understanding of these modifications has potential to identify novel targets to inhibit this devastating disease. Fortunately, the inhibitors and mimics targeted towards histone modification, DNA methylation, and miRNAs are now being tried for cancer and other chronic diseases, and better understanding of the role of epigenetics in diabetic retinopathy will open the door for their possible use in combating this blinding disease.

  17. Epigenetic patterns newly established after interspecific hybridization in natural populations of Solanum

    Science.gov (United States)

    Cara, Nicolás; Marfil, Carlos F; Masuelli, Ricardo W

    2013-01-01

    Interspecific hybridization is known for triggering genetic and epigenetic changes, such as modifications on DNA methylation patterns and impact on phenotypic plasticity and ecological adaptation. Wild potatoes (Solanum, section Petota) are adapted to multiple habitats along the Andes, and natural hybridizations have proven to be a common feature among species of this group. Solanum × rechei, a recently formed hybrid that grows sympatrically with the parental species S. kurtzianum and S. microdontum, represents an ideal model for studying the ecologically and evolutionary importance of hybridization in generating of epigenetic variability. Genetic and epigenetic variability and their correlation with morphological variation were investigated in wild and ex situ conserved populations of these three wild potato species using amplified fragment length polymorphism (AFLP) and methylation-sensitive amplified polymorphism (MSAP) techniques. We observed that novel methylation patterns doubled the number of novel genetic patterns in the hybrid and that the morphological variability measured on 30 characters had a higher correlation with the epigenetic than with the genetic variability. Statistical comparison of methylation levels suggested that the interspecific hybridization induces genome demethylation in the hybrids. A Bayesian analysis of the genetic data reveled the hybrid nature of S. × rechei, with genotypes displaying high levels of admixture with the parental species, while the epigenetic information assigned S. × rechei to its own cluster with low admixture. These findings suggested that after the hybridization event, a novel epigenetic pattern was rapidly established, which might influence the phenotypic plasticity and adaptation of the hybrid to new environments. PMID:24198938

  18. The Microbiological Memory, an Epigenetic Regulator Governing the Balance Between Good Health and Metabolic Disorders

    Directory of Open Access Journals (Sweden)

    Christian A. Devaux

    2018-06-01

    Full Text Available If the transmission of biological information from one generation to the next is based on DNA, most heritable phenotypic traits such as chronic metabolic diseases, are not linked to genetic variation in DNA sequences. Non-genetic heritability might have several causes including epigenetic, parental effect, adaptive social learning, and influence of the ecological environment. Distinguishing among these causes is crucial to resolve major phenotypic enigmas. Strong evidence indicates that changes in DNA expression through various epigenetic mechanisms can be linked to parent-offspring resemblance in terms of sensitivity to metabolic diseases. Among non-genetic heritable traits, early nutrition could account for a long term deviant programming of genes expression responsible for metabolic diseases in adulthood. Nutrition could shape an inadequate gut microbiota (dysbiosis, triggering epigenetic deregulation of transcription which can be observed in chronic metabolic diseases. We review herein the evidence that dysbiosis might be a major cause of heritable epigenetic patterns found to be associated with metabolic diseases. By taking into account the recent advances on the gut microbiome, we have aggregated together different observations supporting the hypothesis that the gut microbiota could promote the molecular crosstalk between bacteria and surrounding host cells which controls the pathological epigenetic signature. We introduce for the first time the concept of “microbiological memory” as the main regulator of the epigenetic signatures, thereby indicating that different causes of non-genetic heritability can interact in complex pathways to produce inheritance.

  19. Epigenetic Alterations in Epstein-Barr Virus-Associated Diseases.

    Science.gov (United States)

    Niller, Hans Helmut; Banati, Ferenc; Salamon, Daniel; Minarovits, Janos

    2016-01-01

    Latent Epstein-Bar virus genomes undergo epigenetic modifications which are dependent on the respective tissue type and cellular phenotype. These define distinct viral epigenotypes corresponding with latent viral gene expression profiles. Viral Latent Membrane Proteins 1 and 2A can induce cellular DNA methyltransferases, thereby influencing the methylation status of the viral and cellular genomes. Therefore, not only the viral genomes carry epigenetic modifications, but also the cellular genomes adopt major epigenetic alterations upon EBV infection. The distinct cellular epigenotypes of EBV-infected cells differ from the epigenotypes of their normal counterparts. In Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC) significant changes in the host cell methylome with a strong tendency towards CpG island hypermethylation are observed. Hypermethylated genes unique for EBVaGC suggest the existence of an EBV-specific "epigenetic signature". Contrary to the primary malignancies carrying latent EBV genomes, lymphoblastoid cells (LCs) established by EBV infection of peripheral B cells in vitro are characterized by a massive genome-wide demethylation and a significant decrease and redistribution of heterochromatic histone marks. Establishing complete epigenomes of the diverse EBV-associated malignancies shall clarify their similarities and differences and further clarify the contribution of EBV to the pathogenesis, especially for the epithelial malignancies, NPC and EBVaGC.

  20. Epigenetic predictor of age.

    Directory of Open Access Journals (Sweden)

    Sven Bocklandt

    Full Text Available From the moment of conception, we begin to age. A decay of cellular structures, gene regulation, and DNA sequence ages cells and organisms. DNA methylation patterns change with increasing age and contribute to age related disease. Here we identify 88 sites in or near 80 genes for which the degree of cytosine methylation is significantly correlated with age in saliva of 34 male identical twin pairs between 21 and 55 years of age. Furthermore, we validated sites in the promoters of three genes and replicated our results in a general population sample of 31 males and 29 females between 18 and 70 years of age. The methylation of three sites--in the promoters of the EDARADD, TOM1L1, and NPTX2 genes--is linear with age over a range of five decades. Using just two cytosines from these loci, we built a regression model that explained 73% of the variance in age, and is able to predict the age of an individual with an average accuracy of 5.2 years. In forensic science, such a model could estimate the age of a person, based on a biological sample alone. Furthermore, a measurement of relevant sites in the genome could be a tool in routine medical screening to predict the risk of age-related diseases and to tailor interventions based on the epigenetic bio-age instead of the chronological age.

  1. Induction of epigenetic variation in Arabidopsis by over-expression of DNA METHYLTRANSFERASE1 (MET1.

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    Samuel Brocklehurst

    Full Text Available Epigenetic marks such as DNA methylation and histone modification can vary among plant accessions creating epi-alleles with different levels of expression competence. Mutations in epigenetic pathway functions are powerful tools to induce epigenetic variation. As an alternative approach, we investigated the potential of over-expressing an epigenetic function, using DNA METHYLTRANSFERASE1 (MET1 for proof-of-concept. In Arabidopsis thaliana, MET1 controls maintenance of cytosine methylation at symmetrical CG positions. At some loci, which contain dense DNA methylation in CG- and non-CG context, loss of MET1 causes joint loss of all cytosines methylation marks. We find that over-expression of both catalytically active and inactive versions of MET1 stochastically generates new epi-alleles at loci encoding transposable elements, non-coding RNAs and proteins, which results for most loci in an increase in expression. Individual transformants share some common phenotypes and genes with altered gene expression. Altered expression states can be transmitted to the next generation, which does not require the continuous presence of the MET1 transgene. Long-term stability and epigenetic features differ for individual loci. Our data show that over-expression of MET1, and potentially of other genes encoding epigenetic factors, offers an alternative strategy to identify epigenetic target genes and to create novel epi-alleles.

  2. Environmentally induced transgenerational epigenetic reprogramming of primordial germ cells and the subsequent germ line.

    Directory of Open Access Journals (Sweden)

    Michael K Skinner

    Full Text Available A number of environmental factors (e.g. toxicants have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. Transgenerational inheritance requires the germline transmission of altered epigenetic information between generations in the absence of direct environmental exposures. The primary periods for epigenetic programming of the germ line are those associated with primordial germ cell development and subsequent fetal germline development. The current study examined the actions of an agricultural fungicide vinclozolin on gestating female (F0 generation progeny in regards to the primordial germ cell (PGC epigenetic reprogramming of the F3 generation (i.e. great-grandchildren. The F3 generation germline transcriptome and epigenome (DNA methylation were altered transgenerationally. Interestingly, disruptions in DNA methylation patterns and altered transcriptomes were distinct between germ cells at the onset of gonadal sex determination at embryonic day 13 (E13 and after cord formation in the testis at embryonic day 16 (E16. A larger number of DNA methylation abnormalities (epimutations and transcriptional alterations were observed in the E13 germ cells than in the E16 germ cells. These observations indicate that altered transgenerational epigenetic reprogramming and function of the male germline is a component of vinclozolin induced epigenetic transgenerational inheritance of disease. Insights into the molecular control of germline transmitted epigenetic inheritance are provided.

  3. Epigenetics in the Vascular Endothelium: Looking From a Different Perspective in the Epigenomics Era.

    Science.gov (United States)

    Yan, Matthew S; Marsden, Philip A

    2015-11-01

    Cardiovascular diseases are commonly thought to be complex, non-Mendelian diseases that are influenced by genetic and environmental factors. A growing body of evidence suggests that epigenetic pathways play a key role in vascular biology and might be involved in defining and transducing cardiovascular disease inheritability. In this review, we argue the importance of epigenetics in vascular biology, especially from the perspective of endothelial cell phenotype. We highlight and discuss the role of epigenetic modifications across the transcriptional unit of protein-coding genes, especially the role of intragenic chromatin modifications, which are underappreciated and not well characterized in the current era of genome-wide studies. Importantly, we describe the practical application of epigenetics in cardiovascular disease therapeutics. © 2015 American Heart Association, Inc.

  4. Transgenerational epigenetics of parental exposure to ionising radiation and other mutagens

    International Nuclear Information System (INIS)

    Dubrova, Yuri E.

    2013-01-01

    Recent studies have established that epigenetic changes play an important role in many common human diseases, including cancer. Given that the epigenetic landscape of the mammalian cell is not fixed and undergoes massive reprogramming during development, it can potentially be affected by a variety of environmental factors. As the majority of the de novo epigenetic marks, including DNA methylation, are faithfully reproduced during DNA replication, they are transmissible through many cell divisions and, in some cases, can be passed from parents to their offspring. An increasing body of experimental evidence from animal and human studies suggests that environmentally-induced epigenetic changes can be inherited by subsequent generations and can result in transgenerational phenotypic alterations, including predisposition to common diseases

  5. Epigenetics and Colorectal Cancer Pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Bardhan, Kankana; Liu, Kebin, E-mail: Kliu@gru.edu [Department of Biochemistry and Molecular Biology, Medical College of Georgia, and Cancer Center, Georgia Regents University, Augusta, GA 30912 (United States)

    2013-06-05

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  6. Genetics and epigenetics of obesity.

    Science.gov (United States)

    Herrera, Blanca M; Keildson, Sarah; Lindgren, Cecilia M

    2011-05-01

    Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40-70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these variants do not fully explain the heritability of obesity, other forms of variation, such as epigenetics marks, must be considered. Epigenetic marks, or "imprinting", affect gene expression without actually changing the DNA sequence. Failures in imprinting are known to cause extreme forms of obesity (e.g. Prader-Willi syndrome), but have also been convincingly associated with susceptibility to obesity. Furthermore, environmental exposures during critical developmental periods can affect the profile of epigenetic marks and result in obesity. We review the most recent evidence for genetic and epigenetic mechanisms involved in the susceptibility and development of obesity. Only a comprehensive understanding of the underlying genetic and epigenetic mechanisms, and the metabolic processes they govern, will allow us to manage, and eventually prevent, obesity. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  7. Transgenerational epigenetics and environmental justice.

    Science.gov (United States)

    Rothstein, Mark A; Harrell, Heather L; Marchant, Gary E

    2017-07-01

    Human transmission to offspring and future generations of acquired epigenetic modifications has not been definitively established, although there are several environmental exposures with suggestive evidence. This article uses three examples of hazardous substances with greater exposures in vulnerable populations: pesticides, lead, and diesel exhaust. It then considers whether, if there were scientific evidence of transgenerational epigenetic inheritance, there would be greater attention given to concerns about environmental justice in environmental laws, regulations, and policies at all levels of government. To provide a broader perspective on environmental justice the article discusses two of the most commonly cited approaches to environmental justice. John Rawls's theory of justice as fairness, a form of egalitarianism, is frequently invoked for the principle that differential treatment of individuals is justified only if actions are designed to benefit those with the greatest need. Another theory, the capabilities approach of Amartya Sen and Martha Nussbaum, focuses on whether essential capabilities of society, such as life and health, are made available to all individuals. In applying principles of environmental justice the article considers whether there is a heightened societal obligation to protect the most vulnerable individuals from hazardous exposures that could adversely affect their offspring through epigenetic mechanisms. It concludes that unless there were compelling evidence of transgenerational epigenetic harms, it is unlikely that there would be a significant impetus to adopt new policies to prevent epigenetic harms by invoking principles of environmental justice.

  8. Epigenetics and colorectal cancer pathogenesis.

    Science.gov (United States)

    Bardhan, Kankana; Liu, Kebin

    2013-06-05

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  9. Epigenetics and Colorectal Cancer Pathogenesis

    International Nuclear Information System (INIS)

    Bardhan, Kankana; Liu, Kebin

    2013-01-01

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy

  10. Epigenetics and Colorectal Cancer Pathogenesis

    Directory of Open Access Journals (Sweden)

    Kebin Liu

    2013-06-01

    Full Text Available Colorectal cancer (CRC develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  11. Epigenetic effects of ionizing radiation

    International Nuclear Information System (INIS)

    EI-Naggar, A.M.

    2007-01-01

    Data generated during the last three decades provide evidence of Epigenetic Effects that ave-induced by ionizing radiation, particularly those of high LET values, and low level dose exposures. Epigenesist is defined as the stepwise process by which genetic information, as modified by environmental influences, is translated into the substance and behavior of cells, tissues, organism.The epigenetic effects cited in the literature are essentially classified into fine types depending on the type and nature of the effect induced.The most accepted postulation, for the occurrence of these epigenetic effects, is a radiation induced bio electric disturbances in the environment of the non-irradiated cellular volume. This will trigger signals that will induce effects in the unirradiated cells.The epigenetic effects referenced in the literature up to date are five types; namely, Genomic Instability, Bystander. Effects, Clastogenic Plasma Factors,, Abscopal Effects, and Tran generational Effects.The demonstration of Epigenetic Effects associated with exposure to ionizing radiation indicates the need to re- examine the concept of radiation dose and target size. Also an improved understanding of qualifiring and quantifying radiation risk estimates may be attained. Also, a more logical means to understand the underlying mechanisms of radiation induced carcinogenic transformation of cells

  12. Epigenetics: a link between addiction and social environment.

    Science.gov (United States)

    Ajonijebu, Duyilemi C; Abboussi, Oualid; Russell, Vivienne A; Mabandla, Musa V; Daniels, William M U

    2017-08-01

    The detrimental effects of drug abuse are apparently not limited to individuals but may also impact the vulnerability of their progenies to develop addictive behaviours. Epigenetic signatures, early life experience and environmental factors, converge to influence gene expression patterns in addiction phenotypes and consequently may serve as mediators of behavioural trait transmission between generations. The majority of studies investigating the role of epigenetics in addiction do not consider the influence of social interactions. This shortcoming in current experimental approaches necessitates developing social models that reflect the addictive behaviour in a free-living social environment. Furthermore, this review also reports on the advancement of interventions for drug addiction and takes into account the emerging roles of histone deacetylase (HDAC) inhibitors in the etiology of drug addiction and that HDAC may be a potential therapeutic target at nucleosomal level to improve treatment outcomes.

  13. Epigenetic changes of DNA repair genes in cancer.

    Science.gov (United States)

    Lahtz, Christoph; Pfeifer, Gerd P

    2011-02-01

    'Every Hour Hurts, The Last One Kills'. That is an old saying about getting old. Every day, thousands of DNA damaging events take place in each cell of our body, but efficient DNA repair systems have evolved to prevent that. However, our DNA repair system and that of most other organisms are not as perfect as that of Deinococcus radiodurans, for example, which is able to repair massive amounts of DNA damage at one time. In many instances, accumulation of DNA damage has been linked to cancer, and genetic deficiencies in specific DNA repair genes are associated with tumor-prone phenotypes. In addition to mutations, which can be either inherited or somatically acquired, epigenetic silencing of DNA repair genes may promote tumorigenesis. This review will summarize current knowledge of the epigenetic inactivation of different DNA repair components in human cancer.

  14. The developmental environment, epigenetic biomarkers and long-term health.

    Science.gov (United States)

    Godfrey, K M; Costello, P M; Lillycrop, K A

    2015-10-01

    Evidence from both human and animal studies has shown that the prenatal and early postnatal environments influence susceptibility to chronic disease in later life and suggests that epigenetic processes are an important mechanism by which the environment alters long-term disease risk. Epigenetic processes, including DNA methylation, histone modification and non-coding RNAs, play a central role in regulating gene expression. The epigenome is highly sensitive to environmental factors in early life, such as nutrition, stress, endocrine disruption and pollution, and changes in the epigenome can induce long-term changes in gene expression and phenotype. In this review we focus on how the early life nutritional environment can alter the epigenome leading to an altered susceptibility to disease in later life.

  15. From linkage studies to epigenetics: what we know and what we need to know in the neurobiology of schizophrenia.

    Directory of Open Access Journals (Sweden)

    Ariel eCariaga-Martinez

    2016-05-01

    Full Text Available Schizophrenia is a complex psychiatric disorder characterized by the presence of positive, negative and cognitive symptoms that lacks a unifying neuropathology. In the present paper, we will review the current understanding of molecular dysregulation in schizophrenia, including genetic and epigenetic studies. In relation to the latter, basic research suggests that normal cognition is regulated by epigenetic mechanisms and its dysfunction occurs upon epigenetic misregulation, providing new insights into missing heritability of complex psychiatric diseases, referring to the discrepancy between epidemiological heritability and the proportion of phenotypic variation explained by DNA sequence difference. In schizophrenia the absence of consistently replicated genetic effects together with evidence for lasting changes in gene expression after environmental exposures suggest a role of epigenetic mechanisms. In this review we will focus on epigenetic modifications as a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of psychotic conditions throughout life.

  16. Epigenetic changes and transposon reactivation in Thai rice hybrids. Molecular Breeding

    NARCIS (Netherlands)

    Kantama, L.; Junbuathong, S.; Sakulkoo, J.; Jong, de J.H.S.G.M.; Apisitwanich, S.

    2013-01-01

    Inter- or intraspecific hybridization is the first step in transferring exogenous traits to the germplasm of a recipient crop. One of the complicating factors is the occurrence of epigenetic modifications of the hybrids, which in turn can change their gene expression and phenotype. In this study we

  17. Epigenetics: A Fascinating Field with Profound Research, Clinical, & Public Health Implications

    Science.gov (United States)

    Stein, Richard A.; Davis, Devra Lee

    2012-01-01

    Epigenetics is emerging as one of the most dynamic and vibrant biomedical areas. Multiple lines of evidence confirm that inherited genetic changes alone cannot fully explain all phenotypic characteristics of live organisms, and additional factors, which are not encoded in the DNA sequence, are involved. The contribution of non-genetic factors is…

  18. Analysis and Optimization of Three-Resonator Wireless Power Transfer System for Predetermined-Goals Wireless Power Transmission

    Directory of Open Access Journals (Sweden)

    Jin Zhang

    2016-04-01

    Full Text Available Three-resonator wireless power transfer (WPT systems have been proposed to improve the power transfer efficiency (PTE and power delivered to the load (PDL in recent years. However, analysis formulas of a three-resonator WPT system are complicated, and the parameters for clarifying the transfer characteristics of this system are difficult to extract. In this paper, concise formulas for analyzing PTE and PDL of the three-resonator system are derived by introducing three factors. Diagram discriminance based on the derived formulas is proposed to obtain the frequency splitting criterions of PTE and PDL in this system. Further, at the transfer distances, where the PTE and PDL are low at original frequency due to frequency splitting phenomenon, the two predetermined-goals of maximizing PTE and PDL are achieved by optimizing coupling strength between the three resonators. The third predetermined-goal of obtaining a constant amount of PDL transfer at maximum PTE is also implemented based on basic algorithms in numerical software. Finally, Simulation and measurement results verify the correctness of analyzing the transfer characteristics of three-resonator WPT system using the presented concise formulas and discriminance. Moreover, effectiveness of realizing the three predetermined-goals via the proposed optimization method is confirmed with experiments.

  19. Systems Analysis Reveals High Genetic and Antigen-Driven Predetermination of Antibody Repertoires throughout B Cell Development

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    Victor Greiff

    2017-05-01

    Full Text Available Antibody repertoire diversity and plasticity is crucial for broad protective immunity. Repertoires change in size and diversity across multiple B cell developmental stages and in response to antigen exposure. However, we still lack fundamental quantitative understanding of the extent to which repertoire diversity is predetermined. Therefore, we implemented a systems immunology framework for quantifying repertoire predetermination on three distinct levels: (1 B cell development (pre-B cell, naive B cell, plasma cell, (2 antigen exposure (three structurally different proteins, and (3 four antibody repertoire components (V-gene usage, clonal expansion, clonal diversity, repertoire size extracted from antibody repertoire sequencing data (400 million reads. Across all three levels, we detected a dynamic balance of high genetic (e.g., >90% for V-gene usage and clonal expansion in naive B cells and antigen-driven (e.g., 40% for clonal diversity in plasma cells predetermination and stochastic variation. Our study has implications for the prediction and manipulation of humoral immunity.

  20. Challenges in reporting on predetermined objectives to the Auditor-General: The case of Limpopo provincial departments

    Directory of Open Access Journals (Sweden)

    Melvin Diedericks

    2017-04-01

    Full Text Available Limpopo provincial departments like all other South African government departments are required to report on performance against predetermined objectives in terms of Section 40 of the Public Finance Management Act 1 of 1999, read in conjunction with Section 5.1.1 of the Treasury Regulations. The purpose of this article is to report on a study that was undertaken to establish the challenges faced by the Limpopo provincial departments in reporting on performance against predetermined objectives to the Auditor-General (AG. Reporting on predetermined objectives has been a challenge over the past financial years and this is evident in the AG’s reports, in which Limpopo provincial departments continued to receive qualified audit reports. The literature review carried out for purposes of this study revealed that performance management is fundamental to enhancing organisational performance. A qualitative research design was used to collect and analyse data. Key findings of the study included that management should prioritise strategic planning, performance reporting, monitoring and evaluation to enable it to be in a position to make a determination as to whether what was planned by the department was actually realised. It is also of paramount importance that performance reporting is highly prioritised at strategic, tactical and operational management meetings to ensure more effective and efficient organisational performance.

  1. Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management.

    Science.gov (United States)

    Zhang, Yingmei; Ren, Jun

    2016-05-01

    Uncorrected obesity has been associated with cardiac hypertrophy and contractile dysfunction. Several mechanisms for this cardiomyopathy have been identified, including oxidative stress, autophagy, adrenergic and renin-angiotensin aldosterone overflow. Another process that may regulate effects of obesity is epigenetics, which refers to the heritable alterations in gene expression or cellular phenotype that are not encoded on the DNA sequence. Advances in epigenome profiling have greatly improved the understanding of the epigenome in obesity, where environmental exposures during early life result in an increased health risk later on in life. Several mechanisms, including histone modification, DNA methylation and non-coding RNAs, have been reported in obesity and can cause transcriptional suppression or activation, depending on the location within the gene, contributing to obesity-induced complications. Through epigenetic modifications, the fetus may be prone to detrimental insults, leading to cardiac sequelae later in life. Important links between epigenetics and obesity include nutrition, exercise, adiposity, inflammation, insulin sensitivity and hepatic steatosis. Genome-wide studies have identified altered DNA methylation patterns in pancreatic islets, skeletal muscle and adipose tissues from obese subjects compared with non-obese controls. In addition, aging and intrauterine environment are associated with differential DNA methylation. Given the intense research on the molecular mechanisms of the etiology of obesity and its complications, this review will provide insights into the current understanding of epigenetics and pharmacological and non-pharmacological (such as exercise) interventions targeting epigenetics as they relate to treatment of obesity and its complications. Particular focus will be on DNA methylation, histone modification and non-coding RNAs. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Early life nutrition, epigenetics and programming of later life disease.

    Science.gov (United States)

    Vickers, Mark H

    2014-06-02

    The global pandemic of obesity and type 2 diabetes is often causally linked to marked changes in diet and lifestyle; namely marked increases in dietary intakes of high energy diets and concomitant reductions in physical activity levels. However, less attention has been paid to the role of developmental plasticity and alterations in phenotypic outcomes resulting from altered environmental conditions during the early life period. Human and experimental animal studies have highlighted the link between alterations in the early life environment and increased risk of obesity and metabolic disorders in later life. This link is conceptualised as the developmental programming hypothesis whereby environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the health and well-being of the offspring. In particular, the nutritional environment in which the fetus or infant develops influences the risk of metabolic disorders in offspring. The late onset of such diseases in response to earlier transient experiences has led to the suggestion that developmental programming may have an epigenetic component, as epigenetic marks such as DNA methylation or histone tail modifications could provide a persistent memory of earlier nutritional states. Moreover, evidence exists, at least from animal models, that such epigenetic programming should be viewed as a transgenerational phenomenon. However, the mechanisms by which early environmental insults can have long-term effects on offspring are relatively unclear. Thus far, these mechanisms include permanent structural changes to the organ caused by suboptimal levels of an important factor during a critical developmental period, changes in gene expression caused by epigenetic modifications (including DNA methylation, histone modification, and microRNA) and permanent changes in cellular ageing. A better understanding of the epigenetic basis of developmental programming and how these effects may be

  3. Early Life Nutrition, Epigenetics and Programming of Later Life Disease

    Directory of Open Access Journals (Sweden)

    Mark H. Vickers

    2014-06-01

    Full Text Available The global pandemic of obesity and type 2 diabetes is often causally linked to marked changes in diet and lifestyle; namely marked increases in dietary intakes of high energy diets and concomitant reductions in physical activity levels. However, less attention has been paid to the role of developmental plasticity and alterations in phenotypic outcomes resulting from altered environmental conditions during the early life period. Human and experimental animal studies have highlighted the link between alterations in the early life environment and increased risk of obesity and metabolic disorders in later life. This link is conceptualised as the developmental programming hypothesis whereby environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the health and well-being of the offspring. In particular, the nutritional environment in which the fetus or infant develops influences the risk of metabolic disorders in offspring. The late onset of such diseases in response to earlier transient experiences has led to the suggestion that developmental programming may have an epigenetic component, as epigenetic marks such as DNA methylation or histone tail modifications could provide a persistent memory of earlier nutritional states. Moreover, evidence exists, at least from animal models, that such epigenetic programming should be viewed as a transgenerational phenomenon. However, the mechanisms by which early environmental insults can have long-term effects on offspring are relatively unclear. Thus far, these mechanisms include permanent structural changes to the organ caused by suboptimal levels of an important factor during a critical developmental period, changes in gene expression caused by epigenetic modifications (including DNA methylation, histone modification, and microRNA and permanent changes in cellular ageing. A better understanding of the epigenetic basis of developmental programming and how

  4. Discussing epigenetics in Southern California

    Science.gov (United States)

    2012-01-01

    With the goal of discussing how epigenetic control and chromatin remodeling contribute to the various processes that lead to cellular plasticity and disease, this symposium marks the collaboration between the Institut National de la Santé et de la Recherche Médicale (INSERM) in France and the University of California, Irvine (UCI). Organized by Paolo Sassone-Corsi (UCI) and held at the Beckman Center of the National Academy of Sciences at the UCI campus December 15–16, 2011, this was the first of a series of international conferences on epigenetics dedicated to the scientific community in Southern California. The meeting also served as the official kick off for the newly formed Center for Epigenetics and Metabolism at the School of Medicine, UCI (http://cem.igb.uci.edu). PMID:22414797

  5. Epigenetics in cancer stem cells.

    Science.gov (United States)

    Toh, Tan Boon; Lim, Jhin Jieh; Chow, Edward Kai-Hua

    2017-02-01

    Compelling evidence have demonstrated that bulk tumors can arise from a unique subset of cells commonly termed "cancer stem cells" that has been proposed to be a strong driving force of tumorigenesis and a key mechanism of therapeutic resistance. Recent advances in epigenomics have illuminated key mechanisms by which epigenetic regulation contribute to cancer progression. In this review, we present a discussion of how deregulation of various epigenetic pathways can contribute to cancer initiation and tumorigenesis, particularly with respect to maintenance and survival of cancer stem cells. This information, together with several promising clinical and preclinical trials of epigenetic modulating drugs, offer new possibilities for targeting cancer stem cells as well as improving cancer therapy overall.

  6. Epigenetic dynamics across the cell cycle

    DEFF Research Database (Denmark)

    Kheir, Tony Bou; Lund, Anders H.

    2010-01-01

    Progression of the mammalian cell cycle depends on correct timing and co-ordination of a series of events, which are managed by the cellular transcriptional machinery and epigenetic mechanisms governing genome accessibility. Epigenetic chromatin modifications are dynamic across the cell cycle...... a correct inheritance of epigenetic chromatin modifications to daughter cells. In this chapter, we summarize the current knowledge on the dynamics of epigenetic chromatin modifications during progression of the cell cycle....

  7. Mitochondrial-epigenetic crosstalk in environmental toxicology.

    Science.gov (United States)

    Weinhouse, Caren

    2017-11-01

    Crosstalk between the nuclear epigenome and mitochondria, both in normal physiological function and in responses to environmental toxicant exposures, is a developing sub-field of interest in environmental and molecular toxicology. The majority (∼99%) of mitochondrial proteins are encoded in the nuclear genome, so programmed communication among nuclear, cytoplasmic, and mitochondrial compartments is essential for maintaining cellular health. In this review, we will focus on correlative and mechanistic evidence for direct impacts of each system on the other, discuss demonstrated or potential crosstalk in the context of chemical insult, and highlight biological research questions for future study. We will first review the two main signaling systems: nuclear signaling to the mitochondria [anterograde signaling], best described in regulation of oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis in response to environmental signals received by the nucleus, and mitochondrial signals to the nucleus [retrograde signaling]. Both signaling systems can communicate intracellular energy needs or a need to compensate for dysfunction to maintain homeostasis, but both can also relay inappropriate signals in the presence of dysfunction in either system and contribute to adverse health outcomes. We will first review these two signaling systems and highlight known or biologically feasible epigenetic contributions to both, then briefly discuss the emerging field of epigenetic regulation of the mitochondrial genome, and finally discuss putative "crosstalk phenotypes", including biological phenomena, such as caloric restriction, maintenance of stemness, and circadian rhythm, and states of disease or loss of function, such as cancer and aging, in which both the nuclear epigenome and mitochondria are strongly implicated. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Epigenetics: a new frontier in dentistry.

    Science.gov (United States)

    Williams, S D; Hughes, T E; Adler, C J; Brook, A H; Townsend, G C

    2014-06-01

    In 2007, only four years after the completion of the Human Genome Project, the journal Science announced that epigenetics was the 'breakthrough of the year'. Time magazine placed it second in the top 10 discoveries of 2009. While our genetic code (i.e. our DNA) contains all of the information to produce the elements we require to function, our epigenetic code determines when and where genes in the genetic code are expressed. Without the epigenetic code, the genetic code is like an orchestra without a conductor. Although there is now a substantial amount of published research on epigenetics in medicine and biology, epigenetics in dental research is in its infancy. However, epigenetics promises to become increasingly relevant to dentistry because of the role it plays in gene expression during development and subsequently potentially influencing oral disease susceptibility. This paper provides a review of the field of epigenetics aimed specifically at oral health professionals. It defines epigenetics, addresses the underlying concepts and provides details about specific epigenetic molecular mechanisms. Further, we discuss some of the key areas where epigenetics is implicated, and review the literature on epigenetics research in dentistry, including its relevance to clinical disciplines. This review considers some implications of epigenetics for the future of dental practice, including a 'personalized medicine' approach to the management of common oral diseases. © 2014 Australian Dental Association.

  9. Epigenetic Epidemiology of Complex Diseases Using Twins

    DEFF Research Database (Denmark)

    Tan, Qihua

    2013-01-01

    through multiple epigenetic mechanisms. This paper reviews the new developments in using twins to study disease-related epigenetic alterations, links them to lifetime environmental exposure with a focus on the discordant twin design and proposes novel data-analytical approaches with the aim of promoting...... a more efficient use of twins in epigenetic studies of complex human diseases....

  10. Investigating the genetic and epigenetic basis of big biological questions with the parthenogenetic marbled crayfish: A review and perspectives.

    Science.gov (United States)

    Vogt, Gunter

    2018-03-01

    In the last 15 years, considerable attempts have been undertaken to develop the obligately parthenogenetic marbled crayfish Procambarus virginalis as a new model in biology. Its main advantage is the production of large numbers of offspring that are genetically identical to the mother, making this crustacean particularly suitable for research in epigenetics. Now, a draft genome, transcriptome and genome-wide methylome are available opening new windows for research. In this article, I summarize the biological advantages and genomic and epigenetic features of marbled crayfish and, based on first promising data, discuss what this new model could contribute to answering of ''big'' biological questions. Genome mining is expected to reveal new insights into the genetic specificities of decapod crustaceans, the genetic basis of arthropod reproduction, moulting and immunity, and more general topics such as the genetic underpinning of adaptation to fresh water, omnivory, biomineralization, sexual system change, behavioural variation, clonal genome evolution, and resistance to cancer. Epigenetic investigations with the marbled crayfish can help clarifying the role of epigenetic mechanisms in gene regulation, tissue specification, adult stem cell regulation, cell ageing, organ regeneration and disease susceptibility. Marbled crayfish is further suitable to elucidate the relationship between genetic and epigenetic variation, the transgenerational inheritance of epigenetic signatures and the contribution of epigenetic phenotype variation to the establishment of social hierarchies, environmental adaptation and speciation. These issues can be tackled by experiments with highly standardized laboratory lineages, comparison of differently adapted wild populations and the generation of genetically and epigenetically edited strains.

  11. Individuality and epigenetics in obesity.

    Science.gov (United States)

    Campión, J; Milagro, F I; Martínez, J A

    2009-07-01

    Excessive weight gain arises from the interactions among environmental factors, genetic predisposition and the individual behavior. However, it is becoming evident that interindividual differences in obesity susceptibility depend also on epigenetic factors. Epigenetics studies the heritable changes in gene expression that do not involve changes to the underlying DNA sequence. These processes include DNA methylation, covalent histone modifications, chromatin folding and, more recently described, the regulatory action of miRNAs and polycomb group complexes. In this review, we focus on experimental evidences concerning dietary factors influencing obesity development by epigenetic mechanisms, reporting treatment doses and durations. Moreover, we present a bioinformatic analysis of promoter regions for the search of future epigenetic biomarkers of obesity, including methylation pattern analyses of several obesity-related genes (epiobesigenes), such as FGF2, PTEN, CDKN1A and ESR1, implicated in adipogenesis, SOCS1/SOCS3, in inflammation, and COX7A1 LPL, CAV1, and IGFBP3, in intermediate metabolism and insulin signalling. The identification of those individuals that at an early age could present changes in the methylation profiles of specific genes could help to predict their susceptibility to later develop obesity, which may allow to prevent and follow-up its progress, as well as to research and develop newer therapeutic approaches.

  12. Epigenetic differences between sister chromatids?

    NARCIS (Netherlands)

    Lansdorp, Peter M.; Falconer, Ester; Tao, Jiang; Brind'Amour, Julie; Naumann, Ulrike; Kanz, L; Fibbe, WE; Lengerke, C; Dick, JE

    2012-01-01

    Semi-conservative replication ensures that the DNA sequence of sister chromatids is identical except for replication errors and variation in the length of telomere repeats resulting from replicative losses and variable end processing. What happens with the various epigenetic marks during DNA

  13. Epigenetic Placental Programming of Preeclampsia

    Science.gov (United States)

    Preeclampsia (PE) affects 8-10% of women in the US and long-term consequences include subsequent development of maternal hypertension and hypertension in offspring. As methylation patterns are established during fetal life, we focused on epigenetic alterations in DNA methylation as a plausible expla...

  14. Circadian clocks, epigenetics, and cancer

    KAUST Repository

    Masri, Selma; Kinouchi, Kenichiro; Sassone-Corsi, Paolo

    2015-01-01

    The interplay between circadian rhythm and cancer has been suggested for more than a decade based on the observations that shift work and cancer incidence are linked. Accumulating evidence implicates the circadian clock in cancer survival and proliferation pathways. At the molecular level, multiple control mechanisms have been proposed to link circadian transcription and cell-cycle control to tumorigenesis.The circadian gating of the cell cycle and subsequent control of cell proliferation is an area of active investigation. Moreover, the circadian clock is a transcriptional system that is intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape at the level of histone modifications, DNA methylation, and small regulatory RNAs are differentially controlled in cancer cells. This concept raises the possibility that epigenetic control is a common thread linking the clock with cancer, though little scientific evidence is known to date.This review focuses on the link between circadian clock and cancer, and speculates on the possible connections at the epigenetic level that could further link the circadian clock to tumor initiation or progression.

  15. Autism Spectrum Disorders and Epigenetics

    Science.gov (United States)

    Grafodatskaya, Daria; Chung, Brian; Szatmari, Peter; Weksberg, Rosanna

    2010-01-01

    Objective: Current research suggests that the causes of autism spectrum disorders (ASD) are multifactorial and include both genetic and environmental factors. Several lines of evidence suggest that epigenetics also plays an important role in ASD etiology and that it might, in fact, integrate genetic and environmental influences to dysregulate…

  16. Epigenetics of the Developing Brain

    Science.gov (United States)

    Champagne, Frances A.

    2015-01-01

    Advances in understanding of the dynamic molecular interplay between DNA and its surrounding proteins suggest that epigenetic mechanisms are a critical link between early life experiences (e.g., prenatal stress, parent-offspring interactions) and long-term changes in brain and behavior. Although much of this evidence comes from animal studies,…

  17. Re: Epigenetics of Cellular Reprogramming

    Directory of Open Access Journals (Sweden)

    Fehmi Narter

    2016-12-01

    Full Text Available EDITORIAL COMMENT Cells have some specific molecular and physiological properties that act their functional process. However, many cells have an ability of efficient transition from one type to another. This ability is named plasticity. This process occurs due to epigenetic reprogramming that involves changes in transcription and chromatin structure. Some changes during reprogramming that have been identified in recent years as genomic demethylation (both histone and DNA, histone acetylation and loss of heterochromatin during the development of many diseases such as infertility and cancer progression. In this review, the authors focused on the latest work addressing the mechanisms surrounding the epigenetic regulation of various types of reprogramming, including somatic cell nuclear transfer, cell fusion and transcription factor- and microRNA-induced pluripotency. There are many responsible factors such as genes, cytokines, proteins, co-factors (i.e. vitamin C in this local area network. The exact mechanisms by which these changes are achieved and the detailed interplay between the players responsible, however, remain relatively unclear. In the treatment of diseases, such as infertility, urooncology, reconstructive urology, etc., epigenetic changes and cellular reprogramming will be crucial in the near future. Central to achieving that goal is a more thorough understanding of the epigenetic state of fully reprogrammed cells. By the progress of researches on this topic, new treatment modalities will be identified for these diseases.

  18. Epigenetics and Therapeutic Targets Mediating Neuroprotection

    Science.gov (United States)

    Qureshi, Irfan A.; Mehler, Mark F.

    2015-01-01

    The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection. In this brief review, we provide an overview of epigenetic mechanisms and highlight the emerging roles played by epigenetic processes in neural cell dysfunction and death and in resultant neuroprotective responses. PMID:26236020

  19. Epigenetic Modifications: Therapeutic Potential in Cancer

    Directory of Open Access Journals (Sweden)

    Manisha Sachan

    2015-08-01

    Full Text Available Epigenetic modifications and alterations in chromatin structure and function contribute to the cumulative changes observed as normal cells undergo malignant transformation. These modifications and enzymes (DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases related to them have been deeply studied to develop new drugs, epigenome-targeted therapies and new diagnostic tools. Epigenetic modifiers aim to restore normal epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. Four of them (azacitidine, decitabine, vorinostat and romidepsin are approved by the U.S. Food and Drug Administration. This article provides an overview about the known functional roles of epigenetic enzymes in cancer development.

  20. Epigenetics in Paediatric Gastroenterology, Hepatology, and Nutrition: Present Trends and Future Perspectives.

    Science.gov (United States)

    Zilbauer, Matthias; Zellos, Aglaia; Heuschkel, Robert; Gasparetto, Marco; Kraiczy, Judith; Postberg, Jan; Greco, Luigi; Auricchio, Renata; Galatola, Martina; Embleton, Nicholas; Wirth, Stefan; Jenke, Andreas

    2016-04-01

    Epigenetics can be defined as stable, potentially heritable changes in the cellular phenotype caused by mechanisms other than alterations to the underlying DNA sequence. As such, any observed phenotypic changes including organ development, aging, and the occurrence of disease could be driven by epigenetic mechanisms in the presence of stable cellular DNA sequences. Indeed, with the exception of rare mutations, the human genome-sequence has remained remarkably stable over the past centuries. In contrast, substantial changes to our environment as part of our modern life style have not only led to a significant reduction of certain infectious diseases but also seen the exponential increase in complex traits including obesity and multifactorial diseases such as autoimmune disorders. It is becoming increasingly clear that epigenetic mechanisms operate at the interface between the genetic code and our environment, and a large body of existing evidence supports the importance of environmental factors such as diet and nutrition, infections, and exposure to toxins on human health. This seems to be particularly the case during vulnerable periods of human development such as pregnancy and early life. Importantly, as the first point of contact for many of such environmental factors including nutrition, the digestive system is being increasingly linked to a number of "modern" pathologies. In this review article, we aim to give a brief introduction to the basic molecular principals of epigenetics and provide a concise summary of the existing evidence for the role of epigenetic mechanisms in gastrointestinal health and disease, hepatology, and nutrition.

  1. Clonal stability and epigenetic variation in sour cherry

    DEFF Research Database (Denmark)

    Clausen, Sabine Karin

    . This observed variability within the clones raises the question as to whether more suitable plant material for the future might be found through similar selection. In this study, a number of the selected individuals were evaluated based on their morphological (harvested yield, number of buds...... selections compared to cl. 'Birgitte'. However, such epigenetic differences may be enough to change gene expression and result in phenotypic variability. This study demonstrates that morphological differences exist both between and within the 'Stevnsbaer' clones 'Birgitte' and 'Viki'. However, the genetic...

  2. Epigenetic modifications and diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Marpadga A. Reddy

    2012-09-01

    Full Text Available Diabetic nephropathy (DN is a major complication associated with both type 1 and type 2 diabetes, and a leading cause of end-stage renal disease. Conventional therapeutic strategies are not fully efficacious in the treatment of DN, suggesting an incomplete understanding of the gene regulation mechanisms involved in its pathogenesis. Furthermore, evidence from clinical trials has demonstrated a “metabolic memory” of prior exposure to hyperglycemia that continues to persist despite subsequent glycemic control. This remains a major challenge in the treatment of DN and other vascular complications. Epigenetic mechanisms such as DNA methylation, nucleosomal histone modifications, and noncoding RNAs control gene expression through regulation of chromatin structure and function and post-transcriptional mechanisms without altering the underlying DNA sequence. Emerging evidence indicates that multiple factors involved in the etiology of diabetes can alter epigenetic mechanisms and regulate the susceptibility to diabetes complications. Recent studies have demonstrated the involvement of histone lysine methylation in the regulation of key fibrotic and inflammatory genes related to diabetes complications including DN. Interestingly, histone lysine methylation persisted in vascular cells even after withdrawal from the diabetic milieu, demonstrating a potential role of epigenetic modifications in metabolic memory. Rapid advances in high-throughput technologies in the fields of genomics and epigenomics can lead to the identification of genome-wide alterations in key epigenetic modifications in vascular and renal cells in diabetes. Altogether, these findings can lead to the identification of potential predictive biomarkers and development of novel epigenetic therapies for diabetes and its associated complications.

  3. Epigenetics in Cancer: A Hematological Perspective.

    Directory of Open Access Journals (Sweden)

    Maximilian Stahl

    2016-10-01

    Full Text Available For several decades, we have known that epigenetic regulation is disrupted in cancer. Recently, an increasing body of data suggests epigenetics might be an intersection of current cancer research trends: next generation sequencing, immunology, metabolomics, and cell aging. The new emphasis on epigenetics is also related to the increasing production of drugs capable of interfering with epigenetic mechanisms and able to trigger clinical responses in even advanced phase patients. In this review, we will use myeloid malignancies as proof of concept examples of how epigenetic mechanisms can trigger or promote oncogenesis. We will also show how epigenetic mechanisms are related to genetic aberrations, and how they affect other systems, like immune response. Finally, we will show how we can try to influence the fate of cancer cells with epigenetic therapy.

  4. Epigenetic Determinism in Science and Society.

    Science.gov (United States)

    Waggoner, Miranda R; Uller, Tobias

    2015-04-03

    The epigenetic "revolution" in science cuts across many disciplines, and it is now one of the fastest growing research areas in biology. Increasingly, claims are made that epigenetics research represents a move away from the genetic determinism that has been prominent both in biological research and in understandings of the impact of biology on society. We discuss to what extent an epigenetic framework actually supports these claims. We show that, in contrast to the received view, epigenetics research is often couched in language as deterministic as genetics research in both science and the popular press. We engage the rapidly emerging conversation about the impact of epigenetics on public discourse and scientific practice, and we contend that the notion of epigenetic determinism - or the belief that epigenetic mechanisms determine the expression of human traits and behaviors - matters for understandings of the influence of biology and society on population health.

  5. The Interaction between the Immune System and Epigenetics in the Etiology of Autism Spectrum Disorders.

    Science.gov (United States)

    Nardone, Stefano; Elliott, Evan

    2016-01-01

    Recent studies have firmly established that the etiology of autism includes both genetic and environmental components. However, we are only just beginning to elucidate the environmental factors that might be involved in the development of autism, as well as the molecular mechanisms through which they function. Mounting epidemiological and biological evidence suggest that prenatal factors that induce a more activated immune state in the mother are involved in the development of autism. In parallel, molecular studies have highlighted the role of epigenetics in brain development as a process susceptible to environmental influences and potentially causative of autism spectrum disorders (ASD). In this review, we will discuss converging evidence for a multidirectional interaction between immune system activation in the mother during pregnancy and epigenetic regulation in the brain of the fetus that may cooperate to produce an autistic phenotype. This interaction includes immune factor-induced changes in epigenetic signatures in the brain, dysregulation of epigenetic modifications specifically in genomic regions that encode immune functions, and aberrant epigenetic regulation of microglia. Overall, the interaction between immune system activation in the mother and the subsequent epigenetic dysregulation in the developing fetal brain may be a main consideration for the environmental factors that cause autism.

  6. The interaction between the immune system and epigenetics in the etiology of autism spectrum disorders

    Directory of Open Access Journals (Sweden)

    Stefano Nardone

    2016-07-01

    Full Text Available Recent studies have firmly established that the etiology of autism includes both genetic and environmental components. However, we are only just beginning to elucidate the environmental factors that might be involved in the development of autism, as well as the molecular mechanisms through which they function. Mounting epidemiological and biological evidence suggest that prenatal factors that induce a more activated immune state in the mother are involved in the development of autism. In parallel, molecular studies have highlighted the role of epigenetics in brain development as process susceptible to environmental influences and potentially causative of ASD. In this review, we will discuss converging evidence for a multidirectional interaction between immune system activation in the mother during pregnancy and epigenetic regulation in the brain of the fetus that may cooperate to produce an autistic phenotype. This interaction includes immune factor-induced changes in epigenetic signatures in the brain, dysregulation of epigenetic modifications specifically in genomic regions that encode immune functions, and aberrant epigenetic regulation of microglia. Overall, the interaction between immune system activation in the mother and the subsequent epigenetic dysregulation in the developing fetal brain may be a main consideration for the environmental factors that cause autism.

  7. [Nutritionnal epigenomics: consequences of unbalanced diets on epigenetics processes of programming during lifespan and between generations].

    Science.gov (United States)

    Junien, C; Gallou-Kabani, C; Vigé, A; Gross, M-S

    2005-04-01

    Epigenetic changes associated with DNA methylation and histone modifications leading to chromatin remodeling and regulation of gene expression underlie the developmental programming of obesity, type 2 diabetes, cardiovascular diseases and metabolic syndrome. This review focuses on converging data supporting the hypothesis that, in addition to "thrifty genotype" inheritance, individuals with obesity, type 2 diabetes, and metabolic syndrome (MetS) with an increased risk of cardiovascular diseases have suffered improper "epigenetic programming" during their fetal/postnatal development due to maternal inadequate nutrition and metabolic disturbances and also during their lifetime, that could even be transmitted to the next generation(s). We highlight the susceptibility of epigenetic mechanisms controlling gene expression to environmental influences due to their inherent malleability, emphasizing the participation of transposable elements and the potential role of imprinted genes during critical time windows in epigenetic programming, from the very beginning of development, throughout life. Increasing our understanding on epigenetic patterns significance and their role in development, evolution and adaptation and on small molecules (nutrients, drugs) that reverse epigenetic (in)activation should provide us with the means to "unlock" silenced (enhanced) genes, and to "convert" the obsolete human thrifty genotype into a "squandering" phenotype.

  8. Epigenetic regulation of serotype expression antagonizes transcriptome dynamics in Paramecium tetraurelia.

    Science.gov (United States)

    Cheaib, Miriam; Dehghani Amirabad, Azim; Nordström, Karl J V; Schulz, Marcel H; Simon, Martin

    2015-08-01

    Phenotypic variation of a single genotype is achieved by alterations in gene expression patterns. Regulation of such alterations depends on their time scale, where short-time adaptations differ from permanently established gene expression patterns maintained by epigenetic mechanisms. In the ciliate Paramecium, serotypes were described for an epigenetically controlled gene expression pattern of an individual multigene family. Paradoxically, individual serotypes can be triggered in Paramecium by alternating environments but are then stabilized by epigenetic mechanisms, thus raising the question to which extend their expression follows environmental stimuli. To characterize environmental adaptation in the context of epigenetically controlled serotype expression, we used RNA-seq to characterize transcriptomes of serotype pure cultures. The resulting vegetative transcriptome resource is first analysed for genes involved in the adaptive response to the altered environment. Secondly, we identified groups of genes that do not follow the adaptive response but show co-regulation with the epigenetically controlled serotype system, suggesting that their gene expression pattern becomes manifested by similar mechanisms. In our experimental set-up, serotype expression and the entire group of co-regulated genes were stable among environmental changes and only heat-shock genes altered expression of these gene groups. The data suggest that the maintenance of these gene expression patterns in a lineage represents epigenetically controlled robustness counteracting short-time adaptation processes. © The Author 2015. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

  9. Comparative epigenomics: an emerging field with breakthrough potential to understand evolution of epigenetic regulation

    Directory of Open Access Journals (Sweden)

    Janine E. Deakin

    2014-12-01

    Full Text Available Epigenetic mechanisms regulate gene expression, thereby mediating the interaction between environment, genotype and phenotype. Changes to epigenetic regulation of genes may be heritable, permitting rapid adaptation of a species to environmental cues. However, most of the current understanding of epigenetic gene regulation has been gained from studies of mice and humans, with only a limited understanding of the conservation of epigenetic mechanisms across divergent taxa. The relative ease at which genome sequence data is now obtained and the advancements made in epigenomics techniques for non-model species provides a basis for carrying out comparative epigenomic studies across a wider range of species, making it possible to start unraveling the evolution of epigenetic mechanisms. We review the current knowledge of epigenetic mechanisms obtained from studying model organisms, give an example of how comparative epigenomics using non-model species is helping to trace the evolutionary history of X chromosome inactivation in mammals and explore the opportunities to study comparative epigenomics in biological systems displaying adaptation between species, such as the immune system and sex determination.

  10. RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dnmt2.

    Directory of Open Access Journals (Sweden)

    Jafar Kiani

    2013-05-01

    Full Text Available RNA-mediated transmission of phenotypes is an important way to explain non-Mendelian heredity. We have previously shown that small non-coding RNAs can induce hereditary epigenetic variations in mice and act as the transgenerational signalling molecules. Two prominent examples for these paramutations include the epigenetic modulation of the Kit gene, resulting in altered fur coloration, and the modulation of the Sox9 gene, resulting in an overgrowth phenotype. We now report that expression of the Dnmt2 RNA methyltransferase is required for the establishment and hereditary maintenance of both paramutations. Our data show that the Kit paramutant phenotype was not transmitted to the progeny of Dnmt2(-/- mice and that the Sox9 paramutation was also not established in Dnmt2(-/- embryos. Similarly, RNA from Dnmt2-negative Kit heterozygotes did not induce the paramutant phenotype when microinjected into Dnmt2-deficient fertilized eggs and microinjection of the miR-124 microRNA failed to induce the characteristic giant phenotype. In agreement with an RNA-mediated mechanism of inheritance, no change was observed in the DNA methylation profiles of the Kit locus between the wild-type and paramutant mice. RNA bisulfite sequencing confirmed Dnmt2-dependent tRNA methylation in mouse sperm and also indicated Dnmt2-dependent cytosine methylation in Kit RNA in paramutant embryos. Together, these findings uncover a novel function of Dnmt2 in RNA-mediated epigenetic heredity.

  11. Epigenetics: The New Frontier in the Landscape of Asthma

    Science.gov (United States)

    Chogtu, Bharti; Bhattacharjee, Dipanjan; Magazine, Rahul

    2016-01-01

    Over the years, on a global scale, asthma has continued to remain one of the leading causes of morbidity, irrespective of age, sex, or social bearings. This is despite the prevalence of varied therapeutic options to counter the pathogenesis of asthma. Asthma, as a disease per se, is a very complex one. Scientists all over the world have been trying to obtain a lucid understanding of the machinations behind asthma. This has led to many theories and conjectures. However, none of the scientific disciplines have been able to provide the missing links in the chain of asthma pathogenesis. This was until epigenetics stepped into the picture. Though epigenetic research in asthma is in its nascent stages, it has led to very exciting results, especially with regard to explaining the massive influence of environment on development of asthma and its varied phenotypes. However, there remains a lot of work to be done, especially with regard to understanding how the interactions between immune system, epigenome, and environment lead to asthma. But introduction of epigenetics has infused a fresh lease of life in research into asthma and the mood among the scientific community is that of cautious optimism. PMID:27293973

  12. Epigenetics: The New Frontier in the Landscape of Asthma

    Directory of Open Access Journals (Sweden)

    Bharti Chogtu

    2016-01-01

    Full Text Available Over the years, on a global scale, asthma has continued to remain one of the leading causes of morbidity, irrespective of age, sex, or social bearings. This is despite the prevalence of varied therapeutic options to counter the pathogenesis of asthma. Asthma, as a disease per se, is a very complex one. Scientists all over the world have been trying to obtain a lucid understanding of the machinations behind asthma. This has led to many theories and conjectures. However, none of the scientific disciplines have been able to provide the missing links in the chain of asthma pathogenesis. This was until epigenetics stepped into the picture. Though epigenetic research in asthma is in its nascent stages, it has led to very exciting results, especially with regard to explaining the massive influence of environment on development of asthma and its varied phenotypes. However, there remains a lot of work to be done, especially with regard to understanding how the interactions between immune system, epigenome, and environment lead to asthma. But introduction of epigenetics has infused a fresh lease of life in research into asthma and the mood among the scientific community is that of cautious optimism.

  13. Epigenetic Mechanisms in Developmental Alcohol-Induced Neurobehavioral Deficits

    Directory of Open Access Journals (Sweden)

    Balapal S. Basavarajappa

    2016-04-01

    Full Text Available Alcohol consumption during pregnancy and its damaging consequences on the developing infant brain are significant public health, social, and economic issues. The major distinctive features of prenatal alcohol exposure in humans are cognitive and behavioral dysfunction due to damage to the central nervous system (CNS, which results in a continuum of disarray that is collectively called fetal alcohol spectrum disorder (FASD. Many rodent models have been developed to understand the mechanisms of and to reproduce the human FASD phenotypes. These animal FASD studies have provided several molecular pathways that are likely responsible for the neurobehavioral abnormalities that are associated with prenatal alcohol exposure of the developing CNS. Recently, many laboratories have identified several immediate, as well as long-lasting, epigenetic modifications of DNA methylation, DNA-associated histone proteins and microRNA (miRNA biogenesis by using a variety of epigenetic approaches in rodent FASD models. Because DNA methylation patterns, DNA-associated histone protein modifications and miRNA-regulated gene expression are crucial for synaptic plasticity and learning and memory, they can therefore offer an answer to many of the neurobehavioral abnormalities that are found in FASD. In this review, we briefly discuss the current literature of DNA methylation, DNA-associated histone proteins modification and miRNA and review recent developments concerning epigenetic changes in FASD.

  14. Imaging epigenetics in Alzheimer's disease.

    Science.gov (United States)

    Lista, Simone; Garaci, Francesco G; Toschi, Nicola; Hampel, Harald

    2013-01-01

    Sporadic Alzheimer's disease (AD) is a prevalent, complex and chronically progressive brain disease. Its course is non-linear, dynamic, adaptive to maladaptive, and compensatory to decompensatory, affecting large-scale neural networks through a plethora of mechanistic and signaling pathway alterations that converge into regional and cell type-specific neurodegeneration and, finally, into clinically overt cognitive and behavioral decline. This decline includes reductions in the activities of daily living, quality of life, independence, and life expectancy. Evolving lines of research suggest that epigenetic mechanisms may play a crucial role during AD development and progression. Epigenetics designates molecular mechanisms that alter gene expression without modifications of the genetic code. This topic includes modifications on DNA and histone proteins, the primary elements of chromatin structure. Accumulating evidence has revealed the relevant processes that mediate epigenetic modifications and has begun to elucidate how these processes are apparently dysregulated in AD. This evidence has led to the clarification of the roles of specific classes of therapeutic compounds that affect epigenetic pathways and characteristics of the epigenome. This insight is accompanied by the development of new methods for studying the global patterns of DNA methylation and chromatin alterations. In particular, high-throughput sequencing approaches, such as next-generation DNA sequencing techniques, are beginning to drive the field into the next stage of development. In parallel, genetic imaging is beginning to answer additional questions through its ability to uncover genetic variants, with or without genome-wide significance, that are related to brain structure, function and metabolism, which impact disease risk and fundamental network-based cognitive processes. Neuroimaging measures can further be used to define AD systems and endophenotypes. The integration of genetic neuroimaging

  15. The danger of epigenetics misconceptions (epigenetics and stuff…).

    Science.gov (United States)

    Georgel, Philippe T

    2015-12-01

    Within the past two decades, the fields of chromatin structure and function and transcription regulation research started to fuse and overlap, as evidence mounted to support a very strong regulatory role in gene expression that was associated with histone post-translational modifications, DNA methylation, as well as various chromatin-associated proteins (the pillars of the "Epigenetics" building). The fusion and convergence of these complementary fields is now often simply referred to as "Epigenetics". During these same 20 years, numerous new research groups have started to recognize the importance of chromatin composition, conformation, and its plasticity. However, as the field started to grow exponentially, its growth came with the spreading of several important misconceptions, which have unfortunately led to improper or hasty conclusions. The goal of this short "opinion" piece is to attempt to minimize future misinterpretations of experimental results and ensure that the right sets of experiment are used to reach the proper conclusion, at least as far as epigenetic mechanisms are concerned.

  16. A Capacity-Restraint Transit Assignment Model When a Predetermination Method Indicates the Invalidity of Time Independence

    Directory of Open Access Journals (Sweden)

    Haoyang Ding

    2015-01-01

    Full Text Available The statistical independence of time of every two adjacent bus links plays a crucial role in deciding the feasibility of using many mathematical models to analyze urban transit networks. Traditional research generally ignores the time independence that acts as the ground of their models. Assumption is usually made that time independence of every two adjacent links is sound. This is, however, actually groundless and probably causes problematic conclusions reached by corresponding models. Many transit assignment models such as multinomial probit-based models lose their effects when the time independence is not valid. In this paper, a simple method to predetermine the time independence is proposed. Based on the predetermination method, a modified capacity-restraint transit assignment method aimed at engineering practice is put forward and tested through a small contrived network and a case study in Nanjing city, China, respectively. It is found that the slope of regression equation between the mean and standard deviation of normal distribution acts as the indicator of time independence at the same time. Besides, our modified assignment method performs better than the traditional one with more reasonable results while keeping the property of simplicity well.

  17. Customizing elastic pressure bandages for reuse to a predetermined, sub-bandage pressure: A randomized controlled trial.

    Science.gov (United States)

    Sermsathanasawadi, Nuttawut; Tarapongpun, Tanakorn; Pianchareonsin, Rattana; Puangpunngam, Nattawut; Wongwanit, Chumpol; Chinsakchai, Khamin; Mutirangura, Pramook; Ruangsetakit, Chanean

    2017-01-01

    Objective A randomized clinical trial was performed to compare the effectiveness of unmarked bandages and customized bandages with visual markers in reproducing the desired sub-bandage pressure during self-bandaging by patients. Method Ninety patients were randomly allocated to two groups ("customized bandages" and "unmarked bandages") and asked to perform self-bandaging three times. The achievement of a pressure between 35 and 45 mmHg in at least two of the three attempts was defined as adequate quality. Results Adequate quality was achieved by 33.0% when applying the unmarked bandages, and 60.0% when applying the customized bandages ( p = 0.02). Use of the customized bandage and previous experience of bandaging were independent predictors for the achievement of the predetermined sub-bandage pressure ( p = 0.005 and p = 0.021, respectively). Conclusion Customized bandages may achieve predetermined sub-bandage pressures more closely than standard, unmarked, compression bandages. Clinical trials registration ClinicalTrials.gov (NCT02729688). Effectiveness of a Pressure Indicator Guided and a Conventional Bandaging in Treatment of Venous Leg Ulcer. https://clinicaltrials.gov/ct2/show/NCT02729688.

  18. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies.

    Science.gov (United States)

    Partin, Alan W; Van Neste, Leander; Klein, Eric A; Marks, Leonard S; Gee, Jason R; Troyer, Dean A; Rieger-Christ, Kimberly; Jones, J Stephen; Magi-Galluzzi, Cristina; Mangold, Leslie A; Trock, Bruce J; Lance, Raymond S; Bigley, Joseph W; Van Criekinge, Wim; Epstein, Jonathan I

    2014-10-01

    The DOCUMENT multicenter trial in the United States validated the performance of an epigenetic test as an independent predictor of prostate cancer risk to guide decision making for repeat biopsy. Confirming an increased negative predictive value could help avoid unnecessary repeat biopsies. We evaluated the archived, cancer negative prostate biopsy core tissue samples of 350 subjects from a total of 5 urological centers in the United States. All subjects underwent repeat biopsy within 24 months with a negative (controls) or positive (cases) histopathological result. Centralized blinded pathology evaluation of the 2 biopsy series was performed in all available subjects from each site. Biopsies were epigenetically profiled for GSTP1, APC and RASSF1 relative to the ACTB reference gene using quantitative methylation specific polymerase chain reaction. Predetermined analytical marker cutoffs were used to determine assay performance. Multivariate logistic regression was used to evaluate all risk factors. The epigenetic assay resulted in a negative predictive value of 88% (95% CI 85-91). In multivariate models correcting for age, prostate specific antigen, digital rectal examination, first biopsy histopathological characteristics and race the test proved to be the most significant independent predictor of patient outcome (OR 2.69, 95% CI 1.60-4.51). The DOCUMENT study validated that the epigenetic assay was a significant, independent predictor of prostate cancer detection in a repeat biopsy collected an average of 13 months after an initial negative result. Due to its 88% negative predictive value adding this epigenetic assay to other known risk factors may help decrease unnecessary repeat prostate biopsies. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  19. Epigenetic regulation in dental pulp inflammation

    Science.gov (United States)

    Hui, T; Wang, C; Chen, D; Zheng, L; Huang, D; Ye, L

    2016-01-01

    Dental caries, trauma, and other possible factors could lead to injury of the dental pulp. Dental infection could result in immune and inflammatory responses mediated by molecular and cellular events and tissue breakdown. The inflammatory response of dental pulp could be regulated by genetic and epigenetic events. Epigenetic modifications play a fundamental role in gene expression. The epigenetic events might play critical roles in the inflammatory process of dental pulp injury. Major epigenetic events include methylation and acetylation of histones and regulatory factors, DNA methylation, and small non-coding RNAs. Infections and other environmental factors have profound effects on epigenetic modifications and trigger diseases. Despite growing evidences of literatures addressing the role of epigenetics in the field of medicine and biology, very little is known about the epigenetic pathways involved in dental pulp inflammation. This review summarized the current knowledge about epigenetic mechanisms during dental pulp inflammation. Progress in studies of epigenetic alterations during inflammatory response would provide opportunities for the development of efficient medications of epigenetic therapy for pulpitis. PMID:26901577

  20. EPA Workshop on Epigenetics and Cumulative Risk ...

    Science.gov (United States)

    Agenda Download the Workshop Agenda (PDF) The workshop included presentations and discussions by scientific experts pertaining to three topics (i.e., epigenetic changes associated with diverse stressors, key science considerations in understanding epigenetic changes, and practical application of epigenetic tools to address cumulative risks from environmental stressors), to address several questions under each topic, and included an opportunity for attendees to participate in break-out groups, provide comments and ask questions. Workshop Goals The workshop seeks to examine the opportunity for use of aggregate epigenetic change as an indicator in cumulative risk assessment for populations exposed to multiple stressors that affect epigenetic status. Epigenetic changes are specific molecular changes around DNA that alter expression of genes. Epigenetic changes include DNA methylation, formation of histone adducts, and changes in micro RNAs. Research today indicates that epigenetic changes are involved in many chronic diseases (cancer, cardiovascular disease, obesity, diabetes, mental health disorders, and asthma). Research has also linked a wide range of stressors including pollution and social factors with occurrence of epigenetic alterations. Epigenetic changes have the potential to reflect impacts of risk factors across multiple stages of life. Only recently receiving attention is the nexus between the factors of cumulative exposure to environmental

  1. Epigenetics and depression: return of the repressed.

    Science.gov (United States)

    Dalton, Victoria S; Kolshus, Erik; McLoughlin, Declan M

    2014-02-01

    Epigenetics has recently emerged as a potential mechanism by which adverse environmental stimuli can result in persistent changes in gene expression. Epigenetic mechanisms function alongside the DNA sequence to modulate gene expression and ultimately influence protein production. The current review provides an introduction and overview of epigenetics with a particular focus on preclinical and clinical studies relevant to major depressive disorder (MDD). PubMed and Web of Science databases were interrogated from January 1995 up to December 2012 using combinations of search terms, including "epigenetic", "microRNA" and "DNA methylation" cross referenced with "depression", "early life stress" and "antidepressant". There is an association between adverse environmental stimuli, such as early life stress, and epigenetic modification of gene expression. Epigenetic changes have been reported in humans with MDD and may serve as biomarkers to improve diagnosis. Antidepressant treatments appear to reverse or initiate compensatory epigenetic alterations that may be relevant to their mechanism of action. As a narrative review, the current report was interpretive and qualitative in nature. Epigenetic modification of gene expression provides a mechanism for understanding the link between long-term effects of adverse life events and the changes in gene expression that are associated with depression. Although still a developing field, in the future, epigenetic modifications of gene expression may provide novel biomarkers to predict future susceptibility and/or onset of MDD, improve diagnosis, and aid in the development of epigenetics-based therapies for depression. © 2013 Published by Elsevier B.V.

  2. Engrampigenetics: Epigenetics of engram memory cells.

    Science.gov (United States)

    Ripoli, Cristian

    2017-05-15

    For long time, the epidemiology of late-onset sporadic Alzheimer's disease (AD) risk factors has centered on adult life-style. Recent studies have, instead, focused on the role of early life experiences in progression of such disease especially in the context of prenatal and postnatal life. Although no single unfavorable environmental event has been shown to be neither necessary nor sufficient for AD development, it is possible that the sum of several environmentally induced effects, over time, contribute to its pathophysiology through epigenetic mechanisms. Indeed, epigenetic changes are influenced by environmental factors and have been proposed to play a role in multifactorial pathologies such as AD. At the same time, recent findings suggest that epigenetic mechanisms are one method that neurons use to translate transient stimuli into stable memories. Thus, the characteristics of epigenetics being a critical link between the environment and genes and playing a crucial role in memory formation make candidate epigenetic mechanisms a natural substrate for AD research. Indeed, independent groups have reported several epigenetically dysregulated genes in AD models; however, the role of epigenetic mechanisms in AD has remained elusive owing to contradictory results. Here, I propose that restricting the analysis of epigenetic changes specifically to subpopulations of neurons (namely, engram memory cells) might be helpful in understanding the role of the epigenetic process in the memory-related specific epigenetic code and might constitute a new template for therapeutic interventions against AD. Copyright © 2016. Published by Elsevier B.V.

  3. Challenges in reporting on pre-determined objectives to the Auditor-General : the case of Limpopo Provincial Departments / Hilgard Maputle Mawela

    OpenAIRE

    Mawela, Hilgard Maputle

    2015-01-01

    All provincial departments are required to report on pre-determined objectives in terms of Section 40 of the Public Finance Management Act, read in conjunction with Section 5.1.1. of the Treasury Regulations. The purpose of this study was to establish the challenges faced by the Limpopo provincial departments in reporting pre-determined objectives to the Auditor-General. Reporting pre-determined objectives has been a challenge over the past financial years and this is evident in the Audito...

  4. Genetics and epigenetics of eating disorders

    Directory of Open Access Journals (Sweden)

    Yilmaz Z

    2015-03-01

    Full Text Available Zeynep Yilmaz,1 J Andrew Hardaway,1 Cynthia M Bulik1–3 1Department of Psychiatry, 2Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Abstract: Eating disorders (EDs are serious psychiatric conditions influenced by biological, psychological, and sociocultural factors. A better understanding of the genetics of these complex traits and the development of more sophisticated molecular biology tools have advanced our understanding of the etiology of EDs. The aim of this review is to critically evaluate the literature on the genetic research conducted on three major EDs: anorexia nervosa, bulimia nervosa, and binge eating disorder. We will first review the diagnostic criteria, clinical features, prevalence, and prognosis of anorexia nervosa, bulimia nervosa, and binge eating disorder, followed by a review of family, twin, and adoption studies. We then review the history of genetic studies of EDs covering linkage analysis, candidate-gene association studies, genome-wide association studies, and the study of rare variants in EDs. Our review also incorporates a translational perspective by covering animal models of ED-related phenotypes. Finally, we review the nascent field of epigenetics of EDs and a look forward to future directions for ED genetic research. Keywords: anorexia nervosa, binge eating disorder, bulimia nervosa, animal models, genome-wide association studies, high-throughput sequencing

  5. Enduring epigenetic landmarks define the cancer microenvironment

    Science.gov (United States)

    Pidsley, Ruth; Lawrence, Mitchell G.; Zotenko, Elena; Niranjan, Birunthi; Statham, Aaron; Song, Jenny; Chabanon, Roman M.; Qu, Wenjia; Wang, Hong; Richards, Michelle; Nair, Shalima S.; Armstrong, Nicola J.; Nim, Hieu T.; Papargiris, Melissa; Balanathan, Preetika; French, Hugh; Peters, Timothy; Norden, Sam; Ryan, Andrew; Pedersen, John; Kench, James; Daly, Roger J.; Horvath, Lisa G.; Stricker, Phillip; Frydenberg, Mark; Taylor, Renea A.; Stirzaker, Clare; Risbridger, Gail P.; Clark, Susan J.

    2018-01-01

    The growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment. To date, molecular profiling has largely been restricted to the epithelial component of tumors; therefore, features underpinning the persistent protumorigenic phenotype of the tumor microenvironment are unknown. Using whole-genome bisulfite sequencing, we show for the first time that cancer-associated fibroblasts (CAFs) from localized prostate cancer display remarkably distinct and enduring genome-wide changes in DNA methylation, significantly at enhancers and promoters, compared to nonmalignant prostate fibroblasts (NPFs). Differentially methylated regions associated with changes in gene expression have cancer-related functions and accurately distinguish CAFs from NPFs. Remarkably, a subset of changes is shared with prostate cancer epithelial cells, revealing the new concept of tumor-specific epigenome modifications in the tumor and its microenvironment. The distinct methylome of CAFs provides a novel epigenetic hallmark of the cancer microenvironment and promises new biomarkers to improve interpretation of diagnostic samples. PMID:29650553

  6. Epigenetic Effects of Cannabis Exposure

    Science.gov (United States)

    Szutorisz, Henrietta; Hurd, Yasmin L.

    2015-01-01

    The past decade has witnessed a number of societal and political changes that have raised critical questions about the long-term impact of marijuana (Cannabis sativa) that are especially important given the prevalence of its abuse and that potential long-term effects still largely lack scientific data. Disturbances of the epigenome have generally been hypothesized as the molecular machinery underlying the persistent, often tissue-specific transcriptional and behavioral effects of cannabinoids that have been observed within one’s lifetime and even into the subsequent generation. Here, we provide an overview of the current published scientific literature that examined epigenetic effects of cannabinoids. Though mechanistic insights about the epigenome remain sparse, accumulating data in humans and animal models have begun to reveal aberrant epigenetic modifications in brain and the periphery linked to cannabis exposure. Expansion of such knowledge and causal molecular relationships could help provide novel targets for future therapeutic interventions. PMID:26546076

  7. Epigenetic regulation of female puberty.

    Science.gov (United States)

    Lomniczi, Alejandro; Wright, Hollis; Ojeda, Sergio R

    2015-01-01

    Substantial progress has been made in recent years toward deciphering the molecular and genetic underpinnings of the pubertal process. The availability of powerful new methods to interrogate the human genome has led to the identification of genes that are essential for puberty to occur. Evidence has also emerged suggesting that the initiation of puberty requires the coordinated activity of gene sets organized into functional networks. At a cellular level, it is currently thought that loss of transsynaptic inhibition, accompanied by an increase in excitatory inputs, results in the pubertal activation of GnRH release. This concept notwithstanding, a mechanism of epigenetic repression targeting genes required for the pubertal activation of GnRH neurons was recently identified as a core component of the molecular machinery underlying the central restraint of puberty. In this chapter we will discuss the potential contribution of various mechanisms of epigenetic regulation to the hypothalamic control of female puberty. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Computational Micromodel for Epigenetic Mechanisms

    Science.gov (United States)

    Raghavan, Karthika; Ruskin, Heather J.; Perrin, Dimitri; Goasmat, Francois; Burns, John

    2010-01-01

    Characterization of the epigenetic profile of humans since the initial breakthrough on the human genome project has strongly established the key role of histone modifications and DNA methylation. These dynamic elements interact to determine the normal level of expression or methylation status of the constituent genes in the genome. Recently, considerable evidence has been put forward to demonstrate that environmental stress implicitly alters epigenetic patterns causing imbalance that can lead to cancer initiation. This chain of consequences has motivated attempts to computationally model the influence of histone modification and DNA methylation in gene expression and investigate their intrinsic interdependency. In this paper, we explore the relation between DNA methylation and transcription and characterize in detail the histone modifications for specific DNA methylation levels using a stochastic approach. PMID:21152421

  9. Computational micromodel for epigenetic mechanisms.

    LENUS (Irish Health Repository)

    Raghavan, Karthika

    2010-11-01

    Characterization of the epigenetic profile of humans since the initial breakthrough on the human genome project has strongly established the key role of histone modifications and DNA methylation. These dynamic elements interact to determine the normal level of expression or methylation status of the constituent genes in the genome. Recently, considerable evidence has been put forward to demonstrate that environmental stress implicitly alters epigenetic patterns causing imbalance that can lead to cancer initiation. This chain of consequences has motivated attempts to computationally model the influence of histone modification and DNA methylation in gene expression and investigate their intrinsic interdependency. In this paper, we explore the relation between DNA methylation and transcription and characterize in detail the histone modifications for specific DNA methylation levels using a stochastic approach.

  10. ["Atypical" method for understanding dementia. How can studying epigenetics contribute?].

    Science.gov (United States)

    Iwata, Atsushi

    2011-11-01

    The pathological hallmark of neurodegeneration is presence of intra- and extra neuronal inclusion bodies such as Lewy bodies in Parkinson's disease, senile plaques and neurofibrillary tangles in Alzheimer's disease. These are consisted of aggregated conformationally abnormal proteins. The precise mechanism of aggregation remains unknown, but increased expression of aggregation-prone proteins can lead to their aggregation. For example, in Down syndrome, duplication of the 21(st) chromosome, which contains the amyloid beta precursor protein (APP) gene, leads to accumulation of amyloid beta and Alzheimer's disease pathology and multiplication of APP gene is shown to be the cause of familial Alzheimer's disease. Moreover, in rare cases of PD, duplication or triplication of SNCA gene leads to alpha-synuclein accumulation, with triplication producing a more severe phenotype than duplication, suggesting that SNCA expression level determines the severity of the pathology. Lastly, animal models of neurodegenerative disorders are generated by over-expression of causal genes, further supporting the conclusion that increased gene expression is related to pathogenesis. Additional evidence indicates that SNCA promoter polymorphisms increases alpha-synuclein expression and increases susceptibility to sporadic PD. In addition to promoter polymorphisms, epigenetic modification can alter downstream gene expression. Epigenetic regulation includes histone modification and DNA methylation, of which CpG island methylation can be gene-specific; in several different cancers, CpG methylation inhibits binding of the transcription machinery, causing silencing of a specific oncogene, which leads to carcinogenesis. In central nervous system disorders, CpG methylation has been associated with psychiatric disorders, such as autism and schizophrenia. We found several cases of Parkinson's disease with epigenetic abnormality in SNCA gene. Thus, we believe that studying epigenetics can provide

  11. Epigenetic regulation of photoperiodic flowering

    OpenAIRE

    Takeno, Kiyotoshi

    2010-01-01

    The cytidine analogue 5-azacytidine, which causes DNA demethylation, induced flowering in the non-vernalization-requiring plants Perilla frutescens var. crispa, Silene armeria and Pharbitis nil (synonym Ipomoea nil) under non-inductive photoperiodic conditions, suggesting that the expression of photoperiodic flowering-related genes is regulated epigenetically by DNA methylation. The flowering state induced by DNA demethylation was not heritable. Changes in the genome-wide methylation state we...

  12. Chromocentre integrity and epigenetic marks

    Czech Academy of Sciences Publication Activity Database

    Harničarová, Andrea; Galiová-Šustáčková, Gabriela; Legartová, Soňa; Kozubek, Stanislav; Matula, P.; Bártová, Eva

    2010-01-01

    Roč. 169, č. 1 (2010), s. 124-133 ISSN 1047-8477 R&D Projects: GA MŠk ME 919; GA MŠk(CZ) LC06027; GA MŠk(CZ) LC535 Grant - others:GA MŠk(CZ) ME919 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : SUV39h * histone methylation * epigenetics Subject RIV: BO - Biophysics Impact factor: 3.497, year: 2010

  13. Learning epigenetic regulation from mycobacteria

    Directory of Open Access Journals (Sweden)

    Sanjeev Khosla

    2016-01-01

    Full Text Available In a eukaryotic cell, the transcriptional fate of a gene is determined by the profile of the epigenetic modifications it is associated with and the conformation it adopts within the chromatin. Therefore, the function that a cell performs is dictated by the sum total of the chromatin organization and the associated epigenetic modifications of each individual gene in the genome (epigenome. As the function of a cell during development and differentiation is determined by its microenvironment, any factor that can alter this microenvironment should be able to alter the epigenome of a cell. In the study published in Nature Communications (Yaseen [2015] Nature Communications 6:8922 doi: 10.1038/ncomms9922, we show that pathogenic Mycobacterium tuberculosis has evolved strategies to exploit this pliability of the host epigenome for its own survival. We describe the identification of a methyltransferase from M. tuberculosis that functions to modulate the host epigenome by methylating a novel, non-canonical arginine, H3R42 in histone H3. In another study, we showed that the mycobacterial protein Rv2966c methylates cytosines present in non-CpG context within host genomic DNA upon infection. Proteins with ability to directly methylate host histones H3 at a novel lysine residue (H3K14 has also been identified from Legionella pnemophilia (RomA. All these studies indicate the use of non-canonical epigenetic mechanisms by pathogenic bacteria to hijack the host transcriptional machinery.

  14. Imbalanced class learning in epigenetics.

    Science.gov (United States)

    Haque, M Muksitul; Skinner, Michael K; Holder, Lawrence B

    2014-07-01

    In machine learning, one of the important criteria for higher classification accuracy is a balanced dataset. Datasets with a large ratio between minority and majority classes face hindrance in learning using any classifier. Datasets having a magnitude difference in number of instances between the target concept result in an imbalanced class distribution. Such datasets can range from biological data, sensor data, medical diagnostics, or any other domain where labeling any instances of the minority class can be time-consuming or costly or the data may not be easily available. The current study investigates a number of imbalanced class algorithms for solving the imbalanced class distribution present in epigenetic datasets. Epigenetic (DNA methylation) datasets inherently come with few differentially DNA methylated regions (DMR) and with a higher number of non-DMR sites. For this class imbalance problem, a number of algorithms are compared, including the TAN+AdaBoost algorithm. Experiments performed on four epigenetic datasets and several known datasets show that an imbalanced dataset can have similar accuracy as a regular learner on a balanced dataset.

  15. Epigenetic control of plant immunity.

    Science.gov (United States)

    Alvarez, María E; Nota, Florencia; Cambiagno, Damián A

    2010-07-01

    In eukaryotic genomes, gene expression and DNA recombination are affected by structural chromatin traits. Chromatin structure is shaped by the activity of enzymes that either introduce covalent modifications in DNA and histone proteins or use energy from ATP to disrupt histone-DNA interactions. The genomic 'marks' that are generated by covalent modifications of histones and DNA, or by the deposition of histone variants, are susceptible to being altered in response to stress. Recent evidence has suggested that proteins generating these epigenetic marks play crucial roles in the defence against pathogens. Histone deacetylases are involved in the activation of jasmonic acid- and ethylene-sensitive defence mechanisms. ATP-dependent chromatin remodellers mediate the constitutive repression of the salicylic acid-dependent pathway, whereas histone methylation at the WRKY70 gene promoter affects the activation of this pathway. Interestingly, bacterial-infected tissues show a net reduction in DNA methylation, which may affect the disease resistance genes responsible for the surveillance against pathogens. As some epigenetic marks can be erased or maintained and transmitted to offspring, epigenetic mechanisms may provide plasticity for the dynamic control of emerging pathogens without the generation of genomic lesions.

  16. Towards a systemic paradigm in carcinogenesis: linking epigenetics and genetics.

    Science.gov (United States)

    Burgio, Ernesto; Migliore, Lucia

    2015-04-01

    For at least 30 years cancer has been defined as a genetic disease and explained by the so-called somatic mutation theory (SMT), which has dominated the carcinogenesis field. Criticism of the SMT has recently greatly increased, although still not enough to force all SMT supporters to recognize its limits. Various researchers point out that cancer appears to be a complex process concerning a whole tissue; and that genomic mutations, although variably deleterious and unpredictably important in determining the establishment of the neoplastic phenotype, are not the primary origin for a malignant neoplasia. We attempt to describe the inadequacies of the SMT and demonstrate that epigenetics is a more logical cause of carcinogenesis. Many previous models of carcinogenesis fall into two classes: (i) in which some biological changes inside cells alone lead to malignancy; and (ii) requiring changes in stroma/extracellular matrix. We try to make clear that in the (ii) model genomic instability is induced by persistent signals coming from the microenvironment, provoking epigenetic and genetic modifications in tissue stem cells that can lead to cancer. In this perspective, stochastic mutations of DNA are a critical by-product rather then the primary cause of cancer. Indirect support for such model of carcinogenesis comes from the in vitro and vivo experiments showing apparent 'reversion' of cancer phenotypes obtained via physiological factors of cellular differentiation (cytokines and other signaling molecules) or drugs, even if the key mutations are not 'reversed'.

  17. Epigenetic telomere protection by Drosophila DNA damage response pathways.

    Science.gov (United States)

    Oikemus, Sarah R; Queiroz-Machado, Joana; Lai, KuanJu; McGinnis, Nadine; Sunkel, Claudio; Brodsky, Michael H

    2006-05-01

    Analysis of terminal deletion chromosomes indicates that a sequence-independent mechanism regulates protection of Drosophila telomeres. Mutations in Drosophila DNA damage response genes such as atm/tefu, mre11, or rad50 disrupt telomere protection and localization of the telomere-associated proteins HP1 and HOAP, suggesting that recognition of chromosome ends contributes to telomere protection. However, the partial telomere protection phenotype of these mutations limits the ability to test if they act in the epigenetic telomere protection mechanism. We examined the roles of the Drosophila atm and atr-atrip DNA damage response pathways and the nbs homolog in DNA damage responses and telomere protection. As in other organisms, the atm and atr-atrip pathways act in parallel to promote telomere protection. Cells lacking both pathways exhibit severe defects in telomere protection and fail to localize the protection protein HOAP to telomeres. Drosophila nbs is required for both atm- and atr-dependent DNA damage responses and acts in these pathways during DNA repair. The telomere fusion phenotype of nbs is consistent with defects in each of these activities. Cells defective in both the atm and atr pathways were used to examine if DNA damage response pathways regulate telomere protection without affecting telomere specific sequences. In these cells, chromosome fusion sites retain telomere-specific sequences, demonstrating that loss of these sequences is not responsible for loss of protection. Furthermore, terminally deleted chromosomes also fuse in these cells, directly implicating DNA damage response pathways in the epigenetic protection of telomeres. We propose that recognition of chromosome ends and recruitment of HP1 and HOAP by DNA damage response proteins is essential for the epigenetic protection of Drosophila telomeres. Given the conserved roles of DNA damage response proteins in telomere function, related mechanisms may act at the telomeres of other organisms.

  18. Epigenetics, eh! A meeting summary of the Canadian Conference on Epigenetics.

    Science.gov (United States)

    Rodenhiser, David I; Bérubé, Nathalie G; Mann, Mellissa R W

    2011-10-01

    In May 2011, the Canadian Conference on Epigenetics: Epigenetics Eh! was held in London, Canada. The objectives of this conference were to showcase the breadth of epigenetic research on environment and health across Canada and to provide the catalyst to develop collaborative Canadian epigenetic research opportunities, similar to existing international epigenetic initiatives in the US and Europe. With ten platform sessions and two sessions with over 100 poster presentations, this conference featured cutting-edge epigenetic research, presented by Canadian and international principal investigators and their trainees in the field of epigenetics and chromatin dynamics. An EpigenART competition included ten artists, creating a unique opportunity for artists and scientists to interact and explore their individual interpretations of this scientific discipline. The conference provided a unique venue for a significant cross-section of Canadian epigenetic researchers from diverse disciplines to meet, interact, collaborate and strategize at the national level.

  19. Epigenetics in autism and other neurodevelopmental diseases.

    Science.gov (United States)

    Miyake, Kunio; Hirasawa, Takae; Koide, Tsuyoshi; Kubota, Takeo

    2012-01-01

    Autism was previously thought to be caused by environmental factors. However, genetic factors are now considered to be more contributory to the pathogenesis of autism, based on the recent findings of mutations in the genes which encode synaptic molecules associated with the communication between neurons. Epigenetic is a mechanism that controls gene expression without changing DNA sequence but by changing chromosomal histone modifications and its abnormality is associated with several neurodevelopmental diseases. Since epigenetic modifications are known to be affected by environmental factors such as nutrition, drugs and mental stress, autistic diseases are not only caused by congenital genetic defects, but may also be caused by environmental factors via epigenetic mechanism. In this chapter, we introduce autistic diseases caused by epigenetic failures and discuss epigenetic changes by environmental factors and discuss new treatments for neurodevelopmental diseases based on the recent epigenetic findings.

  20. Epigenetics, autism spectrum, and neurodevelopmental disorders.

    Science.gov (United States)

    Rangasamy, Sampathkumar; D'Mello, Santosh R; Narayanan, Vinodh

    2013-10-01

    Epigenetic marks are modifications of DNA and histones. They are considered to be permanent within a single cell during development, and are heritable across cell division. Programming of neurons through epigenetic mechanisms is believed to be critical in neural development. Disruption or alteration in this process causes an array of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Recent studies have provided evidence for an altered epigenetic landscape in ASDs and demonstrated the central role of epigenetic mechanisms in their pathogenesis. Many of the genes linked to the ASDs encode proteins that are involved in transcriptional regulation and chromatin remodeling. In this review we highlight selected neurodevelopmental disorders in which epigenetic dysregulation plays an important role. These include Rett syndrome, fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, and Kabuki syndrome. For each of these disorders, we discuss how advances in our understanding of epigenetic mechanisms may lead to novel therapeutic approaches.

  1. Using Epigenetic Therapy to Overcome Chemotherapy Resistance.

    Science.gov (United States)

    Strauss, Julius; Figg, William D

    2016-01-01

    It has been known for decades that as cancer progresses, tumors develop genetic alterations, making them highly prone to developing resistance to therapies. Classically, it has been thought that these acquired genetic changes are fixed. This has led to the paradigm of moving from one cancer therapy to the next while avoiding past therapies. However, emerging data on epigenetic changes during tumor progression and use of epigenetic therapies have shown that epigenetic modifications leading to chemotherapy resistance have the potential to be reversible with epigenetic therapy. In fact, promising clinical data exist that treatment with epigenetic agents can diminish chemotherapy resistance in a number of tumor types including chronic myelogenous leukemia, colorectal, ovarian, lung and breast cancer. The potential for epigenetic-modifying drugs to allow for treatment of resistant disease is exciting and clinical trials have just begun to evaluate this area. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  2. Epigenetic alterations of sedimentary rocks at deposits

    International Nuclear Information System (INIS)

    Komarova, G.V.; Kondrat'eva, I.A.; Zelenova, O.I.

    1980-01-01

    Notions are explained, and technique for studying epigenetic alterations of sedimentary rocks at uranium deposits is described. Main types of epigenetic transformations and their mineralogic-geochemical characteristics are considered. Rock alterations, accompanying uranium mineralization, can be related to 2 types: oxidation and reduction. The main mineralogic-geochemical property of oxidation transformations is epigenetic limonitization. Stratal limonitization in primary grey-coloured terrigenic rocks and in epigenetically reduced (pyritized) rocks, as well as in rock, subjected to epigenetic gleying, are characterized. Reduction type of epigenetic transformations is subdivided into sulphidic and non-sulphidic (gley) subtypes. Sulphidic transformations in grey-coloured terrigenic rocks with organic substance of carbonic row, in rocks, containing organic substance of oil row, sulphide transformations of sedimentary rocks, as well as gley transformations, are considered

  3. Epigenetics in Breast and Prostate Cancer

    OpenAIRE

    Wu, Yanyuan; Sarkissyan, Marianna; Vadgama, Jaydutt V.

    2015-01-01

    Most recent investigations into cancer etiology have identified a key role played by epigenetics. Specifically, aberrant DNA and histone modifications which silence tumor suppressor genes or promote oncogenes have been demonstrated in multiple cancer models. While the role of epigenetics in several solid tumor cancers such as colorectal cancer are well established, there is emerging evidence that epigenetics also plays a critical role in breast and prostate cancer. In breast cancer, DNA methy...

  4. Epigenetic impact of curcumin on stroke prevention

    OpenAIRE

    Kalani, Anuradha; Kamat, Pradip K; Kalani, Komal; Tyagi, Neetu

    2014-01-01

    The epigenetic impact of curcumin in stroke and neurodegenerative disorders is curiosity-arousing. It is derived from Curcuma longa (spice), possesses anti-oxidative, anti-inflammatory, anti-lipidemic, neuro-protective and recently shown to exhibit epigenetic modulatory properties. Epigenetic studies include DNA methylation, histone modifications and RNA-based mechanisms which regulate gene expression without altering nucleotide sequences. Curcumin has been shown to affect cancer by altering ...

  5. Merging data from genetic and epigenetic approaches to better understand autistic spectrum disorder.

    Science.gov (United States)

    Grayson, Dennis R; Guidotti, Alessandro

    2016-01-01

    Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is characterized by a wide range of cognitive and behavioral abnormalities. Genetic research has identified large numbers of genes that contribute to ASD phenotypes. There is compelling evidence that environmental factors contribute to ASD through influences that differentially impact the brain through epigenetic mechanisms. Both genetic mutations and epigenetic influences alter gene expression in different cell types of the brain. Mutations impact the expression of large numbers of genes and also have downstream consequences depending on specific pathways associated with the mutation. Environmental factors impact the expression of sets of genes by altering methylation/hydroxymethylation patterns, local histone modification patterns and chromatin remodeling. Herein, we discuss recent developments in the research of ASD with a focus on epigenetic pathways as a complement to current genetic screening.

  6. New insights in oncology: Epi-genetics and cancer stem cells

    International Nuclear Information System (INIS)

    Krutovskikh, V.; Partensky, C.

    2011-01-01

    Cancer is a multi-etiologic, multistage disease with a prevalent genetic component, which happens when a large number of genes, critical for cell growth, death, differentiation, migration, and metabolic plasticity are altered irreversibly, so as to either 'gain' (oncogenes) or 'lose' (tumour suppressors) their function. Recent discoveries have revealed the previously underestimated etiologic importance of multiple epigenetic, that is to say, reversible factors (histone modifications, DNA methylation, non-coding RNA) involved in the transcriptional and post-transcriptional regulation of proteins, indispensable for the control of cancerous phenotype. Stable alterations of epigenetic machinery ('epi-mutations') turn out to play a critical role at different steps of carcinogenesis. In addition, due to substantial recent progress in stem cell biology, the new concept of cancer stem cells has emerged. This, along with newly discovered epigenetic cancer mechanisms, gives rise to a hope to overcome radio- and chemo-resistance and to eradicate otherwise incurable neoplasms. (authors)

  7. A Decade of Exploring the Mammalian Sperm Epigenome: Paternal Epigenetic and Transgenerational Inheritance

    Directory of Open Access Journals (Sweden)

    Alexandre Champroux

    2018-05-01

    Full Text Available The past decade has seen a tremendous increase in interest and progress in the field of sperm epigenetics. Studies have shown that chromatin regulation during male germline development is multiple and complex, and that the spermatozoon possesses a unique epigenome. Its DNA methylation profile, DNA-associated proteins, nucleo-protamine distribution pattern and non-coding RNA set up a unique epigenetic landscape which is delivered, along with its haploid genome, to the oocyte upon fertilization, and therefore can contribute to embryogenesis and to the offspring health. An emerging body of compelling data demonstrates that environmental exposures and paternal lifestyle can change the sperm epigenome and, consequently, may affect both the embryonic developmental program and the health of future generations. This short review will attempt to provide an overview of what is currently known about sperm epigenome and the existence of transgenerational epigenetic inheritance of paternally acquired traits that may contribute to the offspring phenotype.

  8. Identification, replication and characterization of epigenetic remodelling in the aging genome

    DEFF Research Database (Denmark)

    Li, Shuxia; Christiansen, Lene; Christensen, Kaare

    Background: Aging is a complex biological process that involves numerous changes at various levels through remodelling of multiple biological processes and regulatory mechanisms including epigenetics. Recent analysis of the DNA methylome has reported large numbers of epigenetic markers associated......, and by overwhelming age-related methylation in CpG island and demethylation at shore/shelf and open sea. Biological pathway analysis showed that age-dependent methylations were especially involved in cellular signalling activities while demethylations were particularly related to functions of the extracellular matrix....... Conclusion: Extensive epigenetic remodelling in the DNA methylome could be involved in the aging process. The identified age-methylated and demethylated sites displayed differential distribution patterns over genomic regions and were involved in biological pathways closely related to aging phenotypes and age...

  9. Nutrition, epigenetic mechanisms, and human disease

    National Research Council Canada - National Science Library

    Maulik, Nilanjana; Maulik, Gautam

    2011-01-01

    .... The text discusses the basics of nutrigenomics and epigenetic regulation, types of nutrition influencing genetic imprinting, and the role of nutrition in modulating an individual's predisposition to disease...

  10. Introduction to the Special Section on Epigenetics.

    Science.gov (United States)

    Lester, Barry M; Conradt, Elisabeth; Marsit, Carmen

    2016-01-01

    Epigenetics provides the opportunity to revolutionize our understanding of the role of genetics and the environment in explaining human behavior, although the use of epigenetics to study human behavior is just beginning. In this introduction, the authors present the basics of epigenetics in a way that is designed to make this exciting field accessible to a wide readership. The authors describe the history of human behavioral epigenetic research in the context of other disciplines and graphically illustrate the burgeoning of research in the application of epigenetic methods and principles to the study of human behavior. The role of epigenetics in normal embryonic development and the influence of biological and environmental factors altering behavior through epigenetic mechanisms and developmental programming are discussed. Some basic approaches to the study of epigenetics are reviewed. The authors conclude with a discussion of challenges and opportunities, including intervention, as the field of human behavioral epigenetics continue to grow. © 2016 The Authors. Child Development © 2016 Society for Research in Child Development, Inc.

  11. The predetermined sites of examination for tender points in fibromyalgia syndrome are frequently associated with myofascial trigger points

    DEFF Research Database (Denmark)

    Ge, Hongyou; Wang, Ying; Danneskiold-Samsøe, Bente

    2010-01-01

    . PERSPECTIVE: This article underlies the importance of active MTrPs in FMS patients. Most of the TP sites in FMS are MTrPs. Active MTrPs may serve as a peripheral generator of fibromyalgia pain and inactivation of active MTrPs may thus be an alternative for the treatment of FMS.......The aim of this present study is to test the hypotheses that the 18 predetermined sites of examination for tender points (TP sites) in fibromyalgia syndrome (FMS) are myofascial trigger points (MTrPs), and that the induced pain from active MTrPs at TP sites may mimic fibromyalgia pain. Each TP site......), but not latent MTrPs (r = -.001, P = .99), was positively correlated with spontaneous pain intensity in FMS. The current study provides first evidence that pain from active MTrPs at TP sites mimics fibromyalgia pain. MTrPs may relate to generalized increased sensitivity in FMS due to central sensitization...

  12. Pilot program: NRC severe reactor accident incident response training manual: Public protective actions: Predetermined criteria and initial actions

    International Nuclear Information System (INIS)

    Martin, J.A. Jr.; McKenna, T.J.; Miller, C.W.; Hively, L.M.; Sharpe, R.W.; Giitter, J.G.; Watkins, R.M.

    1987-02-01

    This pilot training manual has been written to fill the need for a general text on NRC response to reactor accidents. The manual is intended to be the foundation for a course for all NRC response personnel. Public Protective Actions - Predetermined Criteria and Initial Actions is the fourth in a series of volumes that collectively summarize the US Nuclear Regulatory Commission (NRC) emergency response during severe power reactor accidents and provide necessary background information. This volume reviews public protective action criteria and objectives, their bases and implementation, and the expected public response. Each volume serves, respectively, as the text for a course of instruction in a series of courses for NRC response personnel. These materials do not provide guidance or license requirements for NRC licensees. Each volume is accompanied by an appendix of slides that can be used to present this material. The slides are called out in the text

  13. Accrual of ROCs LECs and REGOs. Phase 3a: pre-determined entitlements to ROCs for small microgenerators

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2005-07-01

    This report describes a proposed scheme to enable microgenerators in the UK to claim Renewable Obligation Certificates (ROCs) on the basis of predetermined estimates of output rather than data from meters. The aim of the scheme, which has been developed following discussions with representatives of the microgeneration community in the UK, is to make it easier for small generators to access to ROCs and thus encourage householders and smaller commercial/business users to install renewable microgeneration technologies. The work was commissioned as part of the review of the Renewables Obligation. The report considers: background information; the Australian scheme for small generating units; eligibility and entitlements; the operation of the scheme; new procedural and legislative requirements; measures to protect and improve the Renewables Obligation; alterative approaches; scheme benefits; and recommendations. An overview of the scheme's key features is given in the report's executive summary.

  14. Conceptual shifts needed to understand the dynamic interactions of genes, environment, epigenetics, social processes, and behavioral choices.

    Science.gov (United States)

    Jackson, Fatimah L C; Niculescu, Mihai D; Jackson, Robert T

    2013-10-01

    Social and behavioral research in public health is often intimately tied to profound, but frequently neglected, biological influences from underlying genetic, environmental, and epigenetic events. The dynamic interplay between the life, social, and behavioral sciences often remains underappreciated and underutilized in addressing complex diseases and disorders and in developing effective remediation strategies. Using a case-study format, we present examples as to how the inclusion of genetic, environmental, and epigenetic data can augment social and behavioral health research by expanding the parameters of such studies, adding specificity to phenotypic assessments, and providing additional internal control in comparative studies. We highlight the important roles of gene-environment interactions and epigenetics as sources of phenotypic change and as a bridge between the life and social and behavioral sciences in the development of robust interdisciplinary analyses.

  15. Epigenetic Matters: The Link between Early Nutrition, Microbiome, and Long-term Health Development

    Directory of Open Access Journals (Sweden)

    Flavia Indrio

    2017-08-01

    Full Text Available Epigenetic modifications are among the most important mechanisms by which environmental factors can influence early cellular differentiation and create new phenotypic traits during pregnancy and within the neonatal period without altering the deoxyribonucleic acid sequence. A number of antenatal and postnatal factors, such as maternal and neonatal nutrition, pollutant exposure, and the composition of microbiota, contribute to the establishment of epigenetic changes that can not only modulate the individual adaptation to the environment but also have an influence on lifelong health and disease by modifying inflammatory molecular pathways and the immune response. Postnatal intestinal colonization, in turn determined by maternal flora, mode of delivery, early skin-to-skin contact and neonatal diet, leads to specific epigenetic signatures that can affect the barrier properties of gut mucosa and their protective role against later insults, thus potentially predisposing to the development of late-onset inflammatory diseases. The aim of this review is to outline the epigenetic mechanisms of programming and development acting within early-life stages and to examine in detail the role of maternal and neonatal nutrition, microbiota composition, and other environmental factors in determining epigenetic changes and their short- and long-term effects.

  16. TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts.

    Science.gov (United States)

    Bernstein, Diana L; Le Lay, John E; Ruano, Elena G; Kaestner, Klaus H

    2015-05-01

    Current strategies to alter disease-associated epigenetic modifications target ubiquitously expressed epigenetic regulators. This approach does not allow specific genes to be controlled in specific cell types; therefore, tools to selectively target epigenetic modifications in the desired cell type and strategies to more efficiently correct aberrant gene expression in disease are needed. Here, we have developed a method for directing DNA methylation to specific gene loci by conjugating catalytic domains of DNA methyltransferases (DNMTs) to engineered transcription activator-like effectors (TALEs). We demonstrated that these TALE-DNMTs direct DNA methylation specifically to the targeted gene locus in human cells. Further, we determined that minimizing direct nucleotide sequence repeats within the TALE moiety permits efficient lentivirus transduction, allowing easy targeting of primary cell types. Finally, we demonstrated that directed DNA methylation with a TALE-DNMT targeting the CDKN2A locus, which encodes the cyclin-dependent kinase inhibitor p16, decreased CDKN2A expression and increased replication of primary human fibroblasts, as intended. Moreover, overexpression of p16 in these cells reversed the proliferative phenotype, demonstrating the specificity of our epigenetic targeting. Together, our results demonstrate that TALE-DNMTs can selectively target specific genes and suggest that this strategy has potential application for the development of locus-specific epigenetic therapeutics.

  17. Radiation-induced genomic instability: Are epigenetic mechanisms the missing link?

    Energy Technology Data Exchange (ETDEWEB)

    Aypar, Umut; Morgan, William F.; Baulch, Janet E.

    2011-02-01

    Purpose: This review examines the evidence for the hypothesis that epigenetics are involved in the initiation and perpetuation of radiation-induced genomic instability (RIGI). Conclusion: In addition to the extensively studied targeted effects of radiation, it is now apparent that non-targeted delayed effects such as RIGI are also important post-irradiation outcomes. In RIGI, unirradiated progeny cells display phenotypic changes at delayed times after radiation of the parental cell. RIGI is thought to be important in the process of carcinogenesis, however, the mechanism by which this occurs remains to be elucidated. In the genomically unstable clones developed by Morgan and colleagues, radiation-induced mutations, double-strand breaks, or changes in mRNA levels alone could not account for the initiation or perpetuation of RIGI. Since changes in the DNA sequence could not fully explain the mechanism of RIGI, inherited epigenetic changes may be involved. Epigenetics are known to play an important role in many cellular processes and epigenetic aberrations can lead to carcinogenesis. Recent studies in the field of radiation biology suggest that the changes in methylation patterns may be involved in RIGI. Together these clues have led us to hypothesize that epigenetics may be the missing link in understanding the mechanism behind RIGI.

  18. Ecological plant epigenetics: Evidence from model and non-model species, and the way forward.

    Science.gov (United States)

    Richards, Christina L; Alonso, Conchita; Becker, Claude; Bossdorf, Oliver; Bucher, Etienne; Colomé-Tatché, Maria; Durka, Walter; Engelhardt, Jan; Gaspar, Bence; Gogol-Döring, Andreas; Grosse, Ivo; van Gurp, Thomas P; Heer, Katrin; Kronholm, Ilkka; Lampei, Christian; Latzel, Vít; Mirouze, Marie; Opgenoorth, Lars; Paun, Ovidiu; Prohaska, Sonja J; Rensing, Stefan A; Stadler, Peter F; Trucchi, Emiliano; Ullrich, Kristian; Verhoeven, Koen J F

    2017-12-01

    Growing evidence shows that epigenetic mechanisms contribute to complex traits, with implications across many fields of biology. In plant ecology, recent studies have attempted to merge ecological experiments with epigenetic analyses to elucidate the contribution of epigenetics to plant phenotypes, stress responses, adaptation to habitat, and range distributions. While there has been some progress in revealing the role of epigenetics in ecological processes, studies with non-model species have so far been limited to describing broad patterns based on anonymous markers of DNA methylation. In contrast, studies with model species have benefited from powerful genomic resources, which contribute to a more mechanistic understanding but have limited ecological realism. Understanding the significance of epigenetics for plant ecology requires increased transfer of knowledge and methods from model species research to genomes of evolutionarily divergent species, and examination of responses to complex natural environments at a more mechanistic level. This requires transforming genomics tools specifically for studying non-model species, which is challenging given the large and often polyploid genomes of plants. Collaboration among molecular geneticists, ecologists and bioinformaticians promises to enhance our understanding of the mutual links between genome function and ecological processes. © 2017 The Authors. Ecology Letters published by CNRS and John Wiley & Sons Ltd.

  19. Homosexuality via canalized sexual development: a testing protocol for a new epigenetic model.

    Science.gov (United States)

    Rice, William R; Friberg, Urban; Gavrilets, Sergey

    2013-09-01

    We recently synthesized and reinterpreted published studies to advance an epigenetic model for the development of homosexuality (HS). The model is based on epigenetic marks laid down in response to the XX vs. XY karyotype in embryonic stem cells. These marks boost sensitivity to testosterone in XY fetuses and lower it in XX fetuses, thereby canalizing sexual development. Our model predicts that a subset of these canalizing epigenetic marks stochastically carry over across generations and lead to mosaicism for sexual development in opposite-sex offspring--the homosexual phenotype being one such outcome. Here, we begin by outlining why HS has been under-appreciated as a commonplace phenomenon in nature, and how this trend is currently being reversed in the field of neurobiology. We next briefly describe our epigenetic model of HS, develop a set of predictions, and describe how epigenetic profiles of human stem cells can provide for a strong test of the model. © 2013 The Authors. Bioessays published by WILEY Periodicals, Inc.

  20. A nursing theory-guided framework for genetic and epigenetic research.

    Science.gov (United States)

    Maki, Katherine A; DeVon, Holli A

    2018-04-01

    The notion that genetics, through natural selection, determines innate traits has led to much debate and divergence of thought on the impact of innate traits on the human phenotype. The purpose of this synthesis was to examine how innate theory informs genetic research and how understanding innate theory through the lens of Martha Rogers' theory of unitary human beings can offer a contemporary view of how innate traits can inform epigenetic and genetic research. We also propose a new conceptual model for genetic and epigenetic research. The philosophical, theoretical, and research literatures were examined for this synthesis. We have merged philosophical and conceptual phenomena from innate theory with the theory of unitary beings into the University of Illinois at Chicago model for genetic and epigenetic research. Innate traits are the cornerstone of the framework but may be modified epigenetically by biological, physiological, psychological, and social determinants as they are transcribed. These modifiers serve as important links between the concept of innate traits and epigenetic modifications, and, like the theory of unitary human beings, the process is understood in the context of individual and environmental interaction that has the potential to evolve as the determinants change. © 2018 John Wiley & Sons Ltd.

  1. Epigenetic Matters: The Link between Early Nutrition, Microbiome, and Long-term Health Development

    Science.gov (United States)

    Indrio, Flavia; Martini, Silvia; Francavilla, Ruggiero; Corvaglia, Luigi; Cristofori, Fernanda; Mastrolia, Salvatore Andrea; Neu, Josef; Rautava, Samuli; Russo Spena, Giovanna; Raimondi, Francesco; Loverro, Giuseppe

    2017-01-01

    Epigenetic modifications are among the most important mechanisms by which environmental factors can influence early cellular differentiation and create new phenotypic traits during pregnancy and within the neonatal period without altering the deoxyribonucleic acid sequence. A number of antenatal and postnatal factors, such as maternal and neonatal nutrition, pollutant exposure, and the composition of microbiota, contribute to the establishment of epigenetic changes that can not only modulate the individual adaptation to the environment but also have an influence on lifelong health and disease by modifying inflammatory molecular pathways and the immune response. Postnatal intestinal colonization, in turn determined by maternal flora, mode of delivery, early skin-to-skin contact and neonatal diet, leads to specific epigenetic signatures that can affect the barrier properties of gut mucosa and their protective role against later insults, thus potentially predisposing to the development of late-onset inflammatory diseases. The aim of this review is to outline the epigenetic mechanisms of programming and development acting within early-life stages and to examine in detail the role of maternal and neonatal nutrition, microbiota composition, and other environmental factors in determining epigenetic changes and their short- and long-term effects. PMID:28879172

  2. [Genetics and epigenetics in autism].

    Science.gov (United States)

    Nakayama, Atsuo; Masaki, Shiego; Aoki, Eiko

    2006-11-01

    Autism is a behaviorally defined syndrome characterized by impaired social interaction and communication, and restricted, stereotyped interests and behaviors. Several lines of evidence support the contention that genetic factors are a large component to autism etiology. However, in spite of vigorous genetic studies, no single causative or susceptibility gene common in autism has been identified. Thus multiple susceptibility genes in interaction are considered to account for the disorder. Furthermore, environmental risk factors can accelerate the autism development of. Recent advances in understanding the epigenetic regulation may shed light on the interaction among multiple genetic factors and environmental factors.

  3. Epigenetic modulators of thyroid cancer.

    Science.gov (United States)

    Rodríguez-Rodero, Sandra; Delgado-Álvarez, Elías; Díaz-Naya, Lucía; Martín Nieto, Alicia; Menéndez Torre, Edelmiro

    2017-01-01

    There are some well known factors involved in the etiology of thyroid cancer, including iodine deficiency, radiation exposure at early ages, or some genetic changes. However, epigenetic modulators that may contribute to development of these tumors and be helpful to for both their diagnosis and treatment have recently been discovered. The currently known changes in DNA methylation, histone modifications, and non-coding RNAs in each type of thyroid carcinoma are reviewed here. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. Epigenetics of dominance for enzyme activity

    Indian Academy of Sciences (India)

    and produce qualitatively different allozymes and the two alleles are expressed equally within and across all three genotypes and and play an equal role in the epigenetics of dominance. Subunit interaction in the heterodimer over a wide range of H+ concentrations accounts for the epigenetics of dominance for ...

  5. Epigenetic Alterations in Alzheimer’s Disease

    Science.gov (United States)

    Sanchez-Mut, Jose V.; Gräff, Johannes

    2015-01-01

    Alzheimer’s disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD. PMID:26734709

  6. The multifaceted interplay between lipids and epigenetics.

    Science.gov (United States)

    Dekkers, Koen F; Slagboom, P Eline; Jukema, J Wouter; Heijmans, Bastiaan T

    2016-06-01

    The interplay between lipids and epigenetic mechanisms has recently gained increased interest because of its relevance for common diseases and most notably atherosclerosis. This review discusses recent advances in unravelling this interplay with a particular focus on promising approaches and methods that will be able to establish causal relationships. Complementary approaches uncovered close links between circulating lipids and epigenetic mechanisms at multiple levels. A characterization of lipid-associated genetic variants suggests that these variants exert their influence on lipid levels through epigenetic changes in the liver. Moreover, exposure of monocytes to lipids persistently alters their epigenetic makeup resulting in more proinflammatory cells. Hence, epigenetic changes can both impact on and be induced by lipids. It is the combined application of technological advances to probe epigenetic modifications at a genome-wide scale and methodological advances aimed at causal inference (including Mendelian randomization and integrative genomics) that will elucidate the interplay between circulating lipids and epigenetics. Understanding its role in the development of atherosclerosis holds the promise of identifying a new category of therapeutic targets, since epigenetic changes are amenable to reversal.

  7. Epigenetic variation in asexually reproducing organisms

    NARCIS (Netherlands)

    Verhoeven, K.J.F.; Preite, V.

    2014-01-01

    The role that epigenetic inheritance can play in adaptation may differ between sexuals and asexuals because (1) the dynamics of adaptation differ under sexual and asexual reproduction and the opportunities offered by epigenetic inheritance may affect these dynamics differently; and (2) in asexual

  8. Epigenetics in breast and prostate cancer.

    Science.gov (United States)

    Wu, Yanyuan; Sarkissyan, Marianna; Vadgama, Jaydutt V

    2015-01-01

    Most recent investigations into cancer etiology have identified a key role played by epigenetics. Specifically, aberrant DNA and histone modifications which silence tumor suppressor genes or promote oncogenes have been demonstrated in multiple cancer models. While the role of epigenetics in several solid tumor cancers such as colorectal cancer are well established, there is emerging evidence that epigenetics also plays a critical role in breast and prostate cancer. In breast cancer, DNA methylation profiles have been linked to hormone receptor status and tumor progression. Similarly in prostate cancer, epigenetic patterns have been associated with androgen receptor status and response to therapy. The regulation of key receptor pathways and activities which affect clinical therapy treatment options by epigenetics renders this field high priority for elucidating mechanisms and potential targets. A new set of methylation arrays are now available to screen epigenetic changes and provide the cutting-edge tools needed to perform such investigations. The role of nutritional interventions affecting epigenetic changes particularly holds promise. Ultimately, determining the causes and outcomes from epigenetic changes will inform translational applications for utilization as biomarkers for risk and prognosis as well as candidates for therapy.

  9. Epigenetics in mammary gland biology and cancer

    Science.gov (United States)

    In the post genome era, the focus has shifted to understanding the mechanisms that regulate the interpretation of the genetic code. "Epigenetics" as a research field is taking center stage. Epigenetics is a term which is now being used throughout the scientific community in different contexts from p...

  10. Developmental systems of plasticity and trans-generational epigenetic inheritance in nematodes.

    Science.gov (United States)

    Serobyan, Vahan; Sommer, Ralf J

    2017-08-01

    Several decades of research provided detailed insight into how genes control development and evolution, whereas recent studies have expanded this purely genetic perspective by presenting strong evidence for environmental and epigenetic influences. We summarize examples of phenotypic plasticity and trans-generational epigenetic inheritance in the nematode model organisms Pristionchus pacificus and Caenorhabditis elegans, which indicate that the response of developmental systems to environmental influences is hardwired into the organismś genome. We argue that genetic programs regulating these organismal-environmental interactions are themselves subject to natural selection. Indeed, macro-evolutionary studies of nematode feeding structures indicate evolutionary trajectories in which plasticity followed by genetic assimilation results in extreme diversity highlighting the role of plasticity as major facilitator of phenotypic diversification. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Epigenetic reprogramming in the porcine germ line

    DEFF Research Database (Denmark)

    Matzen, Sara Maj Hyldig; Croxall, Nicola; Contreras, David A.

    2011-01-01

    BACKGROUND: Epigenetic reprogramming is critical for genome regulation during germ line development. Genome-wide demethylation in mouse primordial germ cells (PGC) is a unique reprogramming event essential for erasing epigenetic memory and preventing the transmission of epimutations to the next...... an increased proportion of cells in G2. CONCLUSIONS: Our study demonstrates that epigenetic reprogramming occurs in pig migratory and gonadal PGC, and establishes the window of time for the occurrence of these events. Reprogramming of histone H3K9me2 and H3K27me3 detected between E15-E21 precedes the dynamic...... DNA demethylation at imprinted loci and DNA repeats between E22-E42. Our findings demonstrate that major epigenetic reprogramming in the pig germ line follows the overall dynamics shown in mice, suggesting that epigenetic reprogramming of germ cells is conserved in mammals. A better understanding...

  12. Peromyscus as a Mammalian Epigenetic Model

    Directory of Open Access Journals (Sweden)

    Kimberly R. Shorter

    2012-01-01

    Full Text Available Deer mice (Peromyscus offer an opportunity for studying the effects of natural genetic/epigenetic variation with several advantages over other mammalian models. These advantages include the ability to study natural genetic variation and behaviors not present in other models. Moreover, their life histories in diverse habitats are well studied. Peromyscus resources include genome sequencing in progress, a nascent genetic map, and >90,000 ESTs. Here we review epigenetic studies and relevant areas of research involving Peromyscus models. These include differences in epigenetic control between species and substance effects on behavior. We also present new data on the epigenetic effects of diet on coat-color using a Peromyscus model of agouti overexpression. We suggest that in terms of tying natural genetic variants with environmental effects in producing specific epigenetic effects, Peromyscus models have a great potential.

  13. Epigenetics reloaded: the single-cell revolution.

    Science.gov (United States)

    Bheda, Poonam; Schneider, Robert

    2014-11-01

    Mechanistically, how epigenetic states are inherited through cellular divisions remains an important open question in the chromatin field and beyond. Defining the heritability of epigenetic states and the underlying chromatin-based mechanisms within a population of cells is complicated due to cell heterogeneity combined with varying levels of stability of these states; thus, efforts must be focused toward single-cell analyses. The approaches presented here constitute the forefront of epigenetics research at the single-cell level using classic and innovative methods to dissect epigenetics mechanisms from the limited material available in a single cell. This review further outlines exciting future avenues of research to address the significance of epigenetic heterogeneity and the contributions of microfluidics technologies to single-cell isolation and analysis. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Epigenetics: the language of the cell?

    Science.gov (United States)

    Huang, Biao; Jiang, Cizhong; Zhang, Rongxin

    2014-02-01

    Epigenetics is one of the most rapidly developing fields of biological research. Breakthroughs in several technologies have enabled the possibility of genome-wide epigenetic research, for example the mapping of human genome-wide DNA methylation. In addition, with the development of various high-throughput and high-resolution sequencing technologies, a large number of functional noncoding RNAs have been identified. Massive studies indicated that these functional ncRNA also play an important role in epigenetics. In this review, we gain inspiration from the recent proposal of the ceRNAs hypothesis. This hypothesis proposes that miRNAs act as a language of communication. Accordingly, we further deduce that all of epigenetics may functionally acquire such a unique language characteristic. In summary, various epigenetic markers may not only participate in regulating cellular processes, but they may also act as the intracellular 'language' of communication and are involved in extensive information exchanges within cell.

  15. G.M. counter and pre-determined dead time; Compteur G.M. et temps mort impose

    Energy Technology Data Exchange (ETDEWEB)

    Lamotte, R; Le Baud, P [Commissariat a l' Energie Atomique, Saclay (France).Centre d' Etudes Nucleaires

    1959-07-01

    This paper is divided into two main parts. - The first section recalls the principle on which a G.M. counter works, and examines the factors which lead to inaccuracies in counting. The concept of dead time, although simple risen associated with the counter alone, becomes complicated as soon as an electronic dead time is introduced to meet the demands of a measurement or an experiment. The resulting dead time, due to the coexistence of these dead times created by a single motivating factor, shows up as a function of certain laws of probability. From the analysis of the various cases of possible combinations, the conditions which must be fulfilled by a system with pre-determined dead time may be determined. This leads to a method for measuring the dead time of a G.M. counter, and the possibility of studying the latter under the utilisation conditions foreseen. - In the second part the principle, construction and characteristics of two systems with pre-determined dead time are discussed. To conclude, a comparison of several experimental results justifies an extension of the possibilities of a G.M. counter used in conjunction with such a system. (author) [French] Deux parties essentielles scindent cet expose. - La premiere partie rappelle le principe de fonctionnement d'un compteur G.M. et examine les facteurs d'imprecisions affectant les comptages. La notion de temps mort, simple quand elle est associee au compteur seul, se complique des qu'intervient un temps mort electronique introduit pour les besoins d'une mesure ou d'une experience. Le temps mort resultant, du a la coexistence de ces temps morts engendres par une meme cause, se manifeste en fonction de certaines lois de probabilites. L'analyse des differents cas de combinaisons possibles permet de preciser les imperatifs auxquels doit repondre un systeme a temps mort impose. Il en decoule une methode de mesure du temps mort d'un compteur G.M. et la possibilite d'etudier celui-ci dans les conditions d

  16. A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro

    Directory of Open Access Journals (Sweden)

    Craig L. Parfett

    2017-06-01

    Full Text Available An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs. effect data extrapolated to human in vivo concentrations. Much direct experimental evidence now shows that disruption of epigenetic processes by chemicals is a carcinogenic mode of action that leads to altered gene functions playing causal roles in cancer initiation and progression. In assessing chemical safety, it would therefore be advantageous to consider an emerging class of carcinogens, the epigenotoxicants, with the ability to change chromatin and/or DNA marks by direct or indirect effects on the activities of enzymes (writers, erasers/editors, remodelers and readers that convey the epigenetic information. Evidence is reviewed supporting a strategy for in vitro hazard identification of carcinogens that induce toxicity through disturbance of functional epigenetic pathways in human somatic cells, leading to inactivated tumour suppressor genes and carcinogenesis. In the context of human cell transformation models, these in vitro pathway measurements ensure high biological relevance to the apical endpoint of cancer. Four causal mechanisms participating in pathways to persistent epigenetic gene silencing were considered: covalent histone modification, nucleosome remodeling, non-coding RNA interaction and DNA methylation. Within these four interacting mechanisms, 25 epigenetic toxicity pathway components (SET1, MLL1, KDM5, G9A, SUV39H1, SETDB1, EZH2, JMJD3, CBX7, CBX8, BMI, SUZ12, HP1, MPP8, DNMT1, DNMT3A, DNMT3B, TET1, MeCP2, SETDB2, BAZ2

  17. Transgenerational epigenetic effects of the endocrine disruptor vinclozolin on pregnancies and female adult onset disease

    OpenAIRE

    Nilsson, Eric E; Anway, Matthew D; Stanfield, Jacob; Skinner, Michael K

    2008-01-01

    Endocrine disruptor exposure during gonadal sex determination was previously found to induce male rat adult onset transgenerational disease (F1–F4 generation), and this was associated with an alteration in the epigenetic (i.e., DNA methylation) programming of the male germ line. The current study was designed to characterize the transgenerational disease phenotypes of the female adult offspring. Pregnant rats (F0 generation) were treated transiently with vinclozolin (i.e., fungicide with anti...

  18. Epigenetic Changes during Hepatic Stellate Cell Activation.

    Directory of Open Access Journals (Sweden)

    Silke Götze

    Full Text Available Hepatic stellate cells (HSC, which can participate in liver regeneration and fibrogenesis, have recently been identified as liver-resident mesenchymal stem cells. During their activation HSC adopt a myofibroblast-like phenotype accompanied by profound changes in the gene expression profile. DNA methylation changes at single genes have been reported during HSC activation and may participate in the regulation of this process, but comprehensive DNA methylation analyses are still missing. The aim of the present study was to elucidate the role of DNA methylation during in vitro activation of HSC.The analysis of DNA methylation changes by antibody-based assays revealed a strong decrease in the global DNA methylation level during culture-induced activation of HSC. To identify genes which may be regulated by DNA methylation, we performed a genome-wide Methyl-MiniSeq EpiQuest sequencing comparing quiescent and early culture-activated HSC. Approximately 400 differentially methylated regions with a methylation change of at least 20% were identified, showing either hypo- or hypermethylation during activation. Further analysis of selected genes for DNA methylation and expression were performed revealing a good correlation between DNA methylation changes and gene expression. Furthermore, global DNA demethylation during HSC activation was investigated by 5-bromo-2-deoxyuridine assay and L-mimosine treatment showing that demethylation was independent of DNA synthesis and thereby excluding a passive DNA demethylation mechanism.In summary, in vitro activation of HSC initiated strong DNA methylation changes, which were associated with gene regulation. These results indicate that epigenetic mechanisms are important for the control of early HSC activation. Furthermore, the data show that global DNA demethylation during activation is based on an active DNA demethylation mechanism.

  19. Universal modeling of weak antilocalization corrections in quasi-two-dimensional electron systems using predetermined return orbitals

    Science.gov (United States)

    Sawada, A.; Koga, T.

    2017-02-01

    We have developed a method to calculate the weak localization and antilocalization corrections based on the real-space simulation, where we provide 147 885 predetermined return orbitals of quasi-two-dimensional electrons with up to 5000 scattering events that are repeatedly used. Our model subsumes that of Golub [L. E. Golub, Phys. Rev. B 71, 235310 (2005), 10.1103/PhysRevB.71.235310] when the Rashba spin-orbit interaction (SOI) is assumed. Our computation is very simple, fast, and versatile, where the numerical results, obtained all at once, cover wide ranges of the magnetic field under various one-electron interactions H' exactly. Thus, it has straightforward extensibility to incorporate interactions other than the Rashba SOI, such as the linear and cubic Dresselhaus SOIs, Zeeman effect, and even interactions relevant to the valley and pseudo spin degrees of freedom, which should provide a unique tool to study new classes of materials like emerging 2D materials. Using our computation, we also demonstrate the robustness of a persistent spin helix state against the cubic Dresselhaus SOI.

  20. Psychobehavioural Factors Are More Strongly Associated with Successful Weight Management Than Predetermined Satiety Effect or Other Characteristics of Diet

    Directory of Open Access Journals (Sweden)

    Leila Karhunen

    2012-01-01

    Full Text Available This study aimed to investigate factors associated with weight management, especially whether satiety value of food as a part of a weight-maintenance diet would affect self-regulation of food intake and weight management. Altogether 82 obese subjects completed the study consisting of weight-loss and weight-maintenance (WM periods. During the WM, subjects were randomized into higher- and lower-satiety food groups. No differences were observed in the changes in body weight, energy intake, or eating behaviour between the groups, even despite the different macronutrient compositions of the diets. However, when regarding all study subjects, success in WM was most strongly associated with a greater increase in the flexible control of eating and experience of greater easiness of WM and control of food intake and a greater decrease in uncontrollable eating and psychological distress. Psychobehavioural factors seem to be more strongly associated with successful weight management than the predetermined satiety effect or other characteristics of the diet.

  1. Pre-disposition and epigenetics govern variation in bacterial survival upon stress.

    Directory of Open Access Journals (Sweden)

    Ming Ni

    Full Text Available Bacteria suffer various stresses in their unpredictable environment. In response, clonal populations may exhibit cell-to-cell variation, hypothetically to maximize their survival. The origins, propagation, and consequences of this variability remain poorly understood. Variability persists through cell division events, yet detailed lineage information for individual stress-response phenotypes is scarce. This work combines time-lapse microscopy and microfluidics to uniformly manipulate the environmental changes experienced by clonal bacteria. We quantify the growth rates and RpoH-driven heat-shock responses of individual Escherichia coli within their lineage context, stressed by low streptomycin concentrations. We observe an increased variation in phenotypes, as different as survival from death, that can be traced to asymmetric division events occurring prior to stress induction. Epigenetic inheritance contributes to the propagation of the observed phenotypic variation, resulting in three-fold increase of the RpoH-driven expression autocorrelation time following stress induction. We propose that the increased permeability of streptomycin-stressed cells serves as a positive feedback loop underlying this epigenetic effect. Our results suggest that stochasticity, pre-disposition, and epigenetic effects are at the source of stress-induced variability. Unlike in a bet-hedging strategy, we observe that cells with a higher investment in maintenance, measured as the basal RpoH transcriptional activity prior to antibiotic treatment, are more likely to give rise to stressed, frail progeny.

  2. Epigenetic Dysregulation in Laryngeal Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Thian-Sze Wong

    2012-01-01

    Full Text Available Laryngeal carcinoma is a common head and neck cancer with poor prognosis. Patients with laryngeal carcinoma usually present late leading to the reduced treatment efficacy and high rate of recurrence. Despite the advance in the use of molecular markers for monitoring human cancers in the past decades, there are still no reliable markers for use to screen laryngeal carcinoma and follow the patients after treatment. Epigenetics emerged as an important field in understanding the biology of the human malignancies. Epigenetic alterations refer to the dysregulation of gene, which do not involve the alterations of the DNA sequence. Major epigenetic changes including methylation imbalance, histone modification, and small RNA dysregulation could play a role in the development of human malignancies. Global epigenetic change is now regarded as a molecular signature of cancer. The characteristics and behavior of a cancer could be predicted based on the specific epigenetic pattern. We here provide a review on the understanding of epigenetic dysregulation in laryngeal carcinoma. Further knowledge on the initiation and progression of laryngeal carcinoma at epigenetic level could promote the translation of the knowledge to clinical use.

  3. Epigenetic Pathways of Oncogenic Viruses: Therapeutic Promises.

    Science.gov (United States)

    El-Araby, Amr M; Fouad, Abdelrahman A; Hanbal, Amr M; Abdelwahab, Sara M; Qassem, Omar M; El-Araby, Moustafa E

    2016-02-01

    Cancerous transformation comprises different events that are both genetic and epigenetic. The ultimate goal for such events is to maintain cell survival and proliferation. This transformation occurs as a consequence of different features such as environmental and genetic factors, as well as some types of infection. Many viral infections are considered to be causative agents of a number of different malignancies. To convert normal cells into cancerous cells, oncogenic viruses must function at the epigenetic level to communicate with their host cells. Oncogenic viruses encode certain epigenetic factors that lead to the immortality and proliferation of infected cells. The epigenetic effectors produced by oncogenic viruses constitute appealing targets to prevent and treat malignant diseases caused by these viruses. In this review, we highlight the importance of epigenetic reprogramming for virus-induced oncogenesis, with special emphasis on viral epigenetic oncoproteins as therapeutic targets. The discovery of molecular components that target epigenetic pathways, especially viral factors, is also discussed. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Environmental chemical exposures and human epigenetics

    Science.gov (United States)

    Hou, Lifang; Zhang, Xiao; Wang, Dong; Baccarelli, Andrea

    2012-01-01

    Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Rapidly growing evidence has linked environmental pollutants with epigenetic variations, including changes in DNA methylation, histone modifications and microRNAs. Environ mental chemicals and epigenetic changes All of these mechanisms are likely to play important roles in disease aetiology, and their modifications due to environmental pollutants might provide further understanding of disease aetiology, as well as biomarkers reflecting exposures to environmental pollutants and/or predicting the risk of future disease. We summarize the findings on epigenetic alterations related to environmental chemical exposures, and propose mechanisms of action by means of which the exposures may cause such epigenetic changes. We discuss opportunities, challenges and future directions for future epidemiology research in environmental epigenomics. Future investigations are needed to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. In addition, there are numerous reports of epigenetic modifications arising following exposure to environmental toxicants, but most have not been directly linked to disease endpoints. To complete our discussion, we also briefly summarize the diseases that have been linked to environmental chemicals-related epigenetic changes. PMID:22253299

  5. Cancer Control and Prevention by Nutrition and Epigenetic Approaches

    OpenAIRE

    Verma, Mukesh

    2012-01-01

    Significance: Epigenetics involves alterations in gene expression without changing the nucleotide sequence. Because some epigenetic changes can be reversed chemically, epigenetics has tremendous implications for disease intervention and treatment. Recent Advances: After epigenetic components in cancer were characterized, genes and pathways are being characterized in other diseases such as diabetes, obesity, and neurological disorders. Observational, experimental, and clinical studies in diffe...

  6. Epigenetic mechanisms in neurological disease.

    Science.gov (United States)

    Jakovcevski, Mira; Akbarian, Schahram

    2012-08-01

    The exploration of brain epigenomes, which consist of various types of DNA methylation and covalent histone modifications, is providing new and unprecedented insights into the mechanisms of neural development, neurological disease and aging. Traditionally, chromatin defects in the brain were considered static lesions of early development that occurred in the context of rare genetic syndromes, but it is now clear that mutations and maladaptations of the epigenetic machinery cover a much wider continuum that includes adult-onset neurodegenerative disease. Here, we describe how recent advances in neuroepigenetics have contributed to an improved mechanistic understanding of developmental and degenerative brain disorders, and we discuss how they could influence the development of future therapies for these conditions.

  7. [Autism and epigenetics. A model of explanation for the understanding of the genesis in autism spectrum disorders].

    Science.gov (United States)

    Arberas, Claudia; Ruggieri, Víctor

    2013-01-01

    Autism spectrum disorders are characterized by impairment of social integration and language development and restricted interests. Autism spectrum disorders manifest during childhood and may have a varying clinical expression over the years related to different therapeutic approaches, behavior-modifying drugs, and environmental factors, among others. So far, the genetic alterations identified are not sufficient to explain the genesis of all these processes, as many of the mutations found are also present in unaffected individuals. Findings on the underlying biological and pathophysiological mechanisms of entities strongly associated with autism spectrum disorders, such as Rett, fragile X, Angelman, and fetal alcohol syndromes, point to the role of epigenetic changes in disorders of neurodevelopment. Epigenetic phenomena are normal biological processes necessary for cell and thus human life, especially related to embryonic development. Different phenomena that affect epigenetic processes (changes that change operation or expression of a gene, without modifying the DNA structure) have also been shown to be important in the genesis of neurodevelopmental disorders. Alterations in the epigenetic mechanism may be reversible, which may explain the variation in the autism phenotype over time. Here we analyze the normal epigenetic mechanisms, autism spectrum disorders, their association with specific entities associated with altered epigenetic mechanisms, and possible therapeutic approaches targeting these alterations.

  8. Phenotypic plasticity and epithelial-to-mesenchymal transition in the behaviour and therapeutic response of oral squamous cell carcinoma.

    Science.gov (United States)

    Vig, Navin; Mackenzie, Ian C; Biddle, Adrian

    2015-10-01

    It is increasingly recognised that phenotypic plasticity, apparently driven by epigenetic mechanisms, plays a key role in tumour behaviour and markedly influences the important processes of therapeutic survival and metastasis. An important source of plasticity in malignancy is epithelial-to-mesenchymal transition (EMT), a common epigenetically controlled event that results in transition of malignant cells between different phenotypic states that confer motility and enhance survival. In this review, we discuss the importance of phenotypic plasticity and its contribution to cellular heterogeneity in oral squamous cell carcinoma with emphasis on aspects of drug resistance and EMT. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. The epigenetic landscape of transgenerational acclimation to ocean warming

    KAUST Repository

    Ryu, Tae Woo; Veilleux, Heather D.; Donelson, Jennifer M.; Munday, Philip L.; Ravasi, Timothy

    2018-01-01

    Epigenetic inheritance is a potential mechanism by which the environment in one generation can influence the performance of future generations1. Rapid climate change threatens the survival of many organisms; however, recent studies show that some species can adjust to climate-related stress when both parents and their offspring experience the same environmental change2,3. Whether such transgenerational acclimation could have an epigenetic basis is unknown. Here, by sequencing the liver genome, methylomes and transcriptomes of the coral reef fish, Acanthochromis polyacanthus, exposed to current day (+0 °C) or future ocean temperatures (+3 °C) for one generation, two generations and incrementally across generations, we identified 2,467 differentially methylated regions (DMRs) and 1,870 associated genes that respond to higher temperatures within and between generations. Of these genes, 193 were significantly correlated to the transgenerationally acclimating phenotypic trait, aerobic scope, with functions in insulin response, energy homeostasis, mitochondrial activity, oxygen consumption and angiogenesis. These genes may therefore play a key role in restoring performance across generations in fish exposed to increased temperatures associated with climate change. Our study is the first to demonstrate a possible association between DNA methylation and transgenerational acclimation to climate change in a vertebrate.

  10. The epigenetic landscape of transgenerational acclimation to ocean warming

    KAUST Repository

    Ryu, Tae Woo

    2018-04-26

    Epigenetic inheritance is a potential mechanism by which the environment in one generation can influence the performance of future generations1. Rapid climate change threatens the survival of many organisms; however, recent studies show that some species can adjust to climate-related stress when both parents and their offspring experience the same environmental change2,3. Whether such transgenerational acclimation could have an epigenetic basis is unknown. Here, by sequencing the liver genome, methylomes and transcriptomes of the coral reef fish, Acanthochromis polyacanthus, exposed to current day (+0 °C) or future ocean temperatures (+3 °C) for one generation, two generations and incrementally across generations, we identified 2,467 differentially methylated regions (DMRs) and 1,870 associated genes that respond to higher temperatures within and between generations. Of these genes, 193 were significantly correlated to the transgenerationally acclimating phenotypic trait, aerobic scope, with functions in insulin response, energy homeostasis, mitochondrial activity, oxygen consumption and angiogenesis. These genes may therefore play a key role in restoring performance across generations in fish exposed to increased temperatures associated with climate change. Our study is the first to demonstrate a possible association between DNA methylation and transgenerational acclimation to climate change in a vertebrate.

  11. Epigenetic silencing of CYP24 in the tumor microenvironment

    Science.gov (United States)

    Johnson, Candace S.; Chung, Ivy; Trump, Donald L.

    2010-01-01

    Calcitriol (1,25 dihydroxycholecalciferol) has significant antitumor activity in vitro and in vivo in a number of tumor model systems. We developed a system for isolation of fresh endothelial cells from tumors and Matrigel environments which demonstrate that CYP24, the catabolic enzyme involved in vitamin D signaling, is epigenetically silenced selectively in tumor-derived endothelial cells (TDEC). TDEC maintain phenotypic characteristics which are distinct from endothelial cells isolated from normal tissues and from Matrigel plugs (MDEC). In TDEC, calcitriol induces G0/G1 arrest, modulates p27 and p21, and induces apoptotic cell death and decreases P-Erk and P-Akt. In contrast, endothelial cells isolated from normal tissues and MDEC are unresponsive to calcitriol-mediated anti-proliferative effects despite intact signaling through the vitamin D receptor (VDR). In TDEC, which is sensitive to calcitriol, the CYP24 promoter is hypermethylated in two CpG island regions located at the 5′end; this hypermethylation may contribute to gene silencing of CYP24. The extent of methylation in these two regions is significantly less in MDEC. Lastly, treatment of TDEC with a DNA methyltransferase inhibitor restores calcitriol-mediated induction of CYP24 and resistance to calcitriol. These data suggest that epigenetic silencing of CYP24 modulates cellular responses to calcitriol. PMID:20304059

  12. A symbiotic liaison between the genetic and epigenetic code

    Directory of Open Access Journals (Sweden)

    Holger eHeyn

    2014-05-01

    Full Text Available With rapid advances in sequencing technologies, we are undergoing a paradigm shift from hypothesis- to data-driven research. Genome-wide profiling efforts gave informative insights into biological processes; however, considering the wealth of variation, the major challenge remains their meaningful interpretation. In particular sequence variation in non-coding contexts is often challenging to interpret. Here, data integration approaches for the identification of functional genetic variability represent a likely solution. Exemplary, functional linkage analysis integrating genotype and expression data determined regulatory quantitative trait loci (QTL and proposed causal relationships. In addition to gene expression, epigenetic regulation and specifically DNA methylation was established as highly valuable surrogate mark for functional variance of the genetic code. Epigenetic modification served as powerful mediator trait to elucidate mechanisms forming phenotypes in health and disease. Particularly, integrative studies of genetic and DNA methylation data yet guided interpretation strategies of risk genotypes, but also proved their value for physiological traits, such as natural human variation and aging. This Perspective seeks to illustrate the power of data integration in the genomic era exemplified by DNA methylation quantitative trait loci (meQTLs. However, the model is further extendable to virtually all traceable molecular traits.

  13. Erwin Schroedinger, Francis Crick and epigenetic stability

    Directory of Open Access Journals (Sweden)

    Ogryzko Vasily V

    2008-04-01

    Full Text Available Abstract Schroedinger's book 'What is Life?' is widely credited for having played a crucial role in development of molecular and cellular biology. My essay revisits the issues raised by this book from the modern perspective of epigenetics and systems biology. I contrast two classes of potential mechanisms of epigenetic stability: 'epigenetic templating' and 'systems biology' approaches, and consider them from the point of view expressed by Schroedinger. I also discuss how quantum entanglement, a nonclassical feature of quantum mechanics, can help to address the 'problem of small numbers' that led Schroedinger to promote the idea of a molecular code-script for explaining the stability of biological order.

  14. Design of small-molecule epigenetic modulators

    Science.gov (United States)

    Pachaiyappan, Boobalan

    2013-01-01

    The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be catagorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. PMID:24300735

  15. Erwin Schroedinger, Francis Crick and epigenetic stability.

    Science.gov (United States)

    Ogryzko, Vasily V

    2008-04-17

    Schroedinger's book 'What is Life?' is widely credited for having played a crucial role in development of molecular and cellular biology. My essay revisits the issues raised by this book from the modern perspective of epigenetics and systems biology. I contrast two classes of potential mechanisms of epigenetic stability: 'epigenetic templating' and 'systems biology' approaches, and consider them from the point of view expressed by Schroedinger. I also discuss how quantum entanglement, a nonclassical feature of quantum mechanics, can help to address the 'problem of small numbers' that led Schroedinger to promote the idea of a molecular code-script for explaining the stability of biological order.

  16. An integrated model of multiple-condition ChIP-Seq data reveals predeterminants of Cdx2 binding.

    Directory of Open Access Journals (Sweden)

    Shaun Mahony

    2014-03-01

    Full Text Available Regulatory proteins can bind to different sets of genomic targets in various cell types or conditions. To reliably characterize such condition-specific regulatory binding we introduce MultiGPS, an integrated machine learning approach for the analysis of multiple related ChIP-seq experiments. MultiGPS is based on a generalized Expectation Maximization framework that shares information across multiple experiments for binding event discovery. We demonstrate that our framework enables the simultaneous modeling of sparse condition-specific binding changes, sequence dependence, and replicate-specific noise sources. MultiGPS encourages consistency in reported binding event locations across multiple-condition ChIP-seq datasets and provides accurate estimation of ChIP enrichment levels at each event. MultiGPS's multi-experiment modeling approach thus provides a reliable platform for detecting differential binding enrichment across experimental conditions. We demonstrate the advantages of MultiGPS with an analysis of Cdx2 binding in three distinct developmental contexts. By accurately characterizing condition-specific Cdx2 binding, MultiGPS enables novel insight into the mechanistic basis of Cdx2 site selectivity. Specifically, the condition-specific Cdx2 sites characterized by MultiGPS are highly associated with pre-existing genomic context, suggesting that such sites are pre-determined by cell-specific regulatory architecture. However, MultiGPS-defined condition-independent sites are not predicted by pre-existing regulatory signals, suggesting that Cdx2 can bind to a subset of locations regardless of genomic environment. A summary of this paper appears in the proceedings of the RECOMB 2014 conference, April 2-5.

  17. Sex differences in prenatal epigenetic programming of stress pathways.

    Science.gov (United States)

    Bale, Tracy L

    2011-07-01

    Maternal stress experience is associated with neurodevelopmental disorders including schizophrenia and autism. Recent studies have examined mechanisms by which changes in the maternal milieu may be transmitted to the developing embryo and potentially translated into programming of the epigenome. Animal models of prenatal stress have identified important sex- and temporal-specific effects on offspring stress responsivity. As dysregulation of stress pathways is a common feature in most neuropsychiatric diseases, molecular and epigenetic analyses at the maternal-embryo interface, especially in the placenta, may provide unique insight into identifying much-needed predictive biomarkers. In addition, as most neurodevelopmental disorders present with a sex bias, examination of sex differences in the inheritance of phenotypic outcomes may pinpoint gene targets and specific windows of vulnerability in neurodevelopment, which have been disrupted. This review discusses the association and possible contributing mechanisms of prenatal stress in programming offspring stress pathway dysregulation and the importance of sex.

  18. Intergenerational epigenetic inheritance in reef-building corals

    KAUST Repository

    Liew, Yi Jin

    2018-02-22

    The notion that intergenerational or transgenerational inheritance operates solely through genetic means is slowly being eroded: epigenetic mechanisms have been shown to induce heritable changes in gene activity in plants and metazoans. Inheritance of DNA methylation provides a potential pathway for environmentally induced phenotypes to contribute to evolution of species and populations. However, in basal metazoans, it is unknown whether inheritance of CpG methylation patterns occurs across the genome (as in plants) or as rare exceptions (as in mammals). Here, we demonstrate genome-wide intergenerational transmission of CpG methylation patterns from parents to sperm and larvae in a reef-building coral. We also show variation in hypermethylated genes in corals from distinct environments, indicative of responses to variations in temperature and salinity. These findings support a role of DNA methylation in the transgenerational inheritance of traits in corals, which may extend to enhancing their capacity to adapt to climate change.

  19. Intergenerational epigenetic inheritance in reef-building corals

    KAUST Repository

    Liew, Yi Jin; Howells, Emily J.; Wang, Xin; Michell, Craig; Burt, John A.; Idaghdour, Youssef; Aranda, Manuel

    2018-01-01

    The notion that intergenerational or transgenerational inheritance operates solely through genetic means is slowly being eroded: epigenetic mechanisms have been shown to induce heritable changes in gene activity in plants and metazoans. Inheritance of DNA methylation provides a potential pathway for environmentally induced phenotypes to contribute to evolution of species and populations. However, in basal metazoans, it is unknown whether inheritance of CpG methylation patterns occurs across the genome (as in plants) or as rare exceptions (as in mammals). Here, we demonstrate genome-wide intergenerational transmission of CpG methylation patterns from parents to sperm and larvae in a reef-building coral. We also show variation in hypermethylated genes in corals from distinct environments, indicative of responses to variations in temperature and salinity. These findings support a role of DNA methylation in the transgenerational inheritance of traits in corals, which may extend to enhancing their capacity to adapt to climate change.

  20. Adjusting to global change through clonal growth and epigenetic variation

    Directory of Open Access Journals (Sweden)

    Richard S Dodd

    2016-07-01

    Full Text Available The earth is experiencing major changes in global and regional climates and changes are predicted to accelerate in the future. Many species will be under considerable pressure to evolve, to migrate, or be faced with extinction. Clonal plants would appear to be at a particular disadvantage due to their limited mobility and limited capacity for adaptation. However, they have outlived previous environmental shifts and clonal species have persisted for millenia. Clonal spread offers unique ecological advantages, such as resource sharing, risk sharing, and economies of scale among ramets within genotypes. We suggest that ecological attributes of clonal plants, in tandem with variation in gene regulation through epigenetic mechanisms that facilitate and optimize phenotype variation in response to environmental change may permit them to be well suited to projected conditions.

  1. Xenopus reduced folate carrier regulates neural crest development epigenetically.

    Directory of Open Access Journals (Sweden)

    Jiejing Li

    Full Text Available Folic acid deficiency during pregnancy causes birth neurocristopathic malformations resulting from aberrant development of neural crest cells. The Reduced folate carrier (RFC is a membrane-bound receptor for facilitating transfer of reduced folate into the cells. RFC knockout mice are embryonic lethal and develop multiple malformations, including neurocristopathies. Here we show that XRFC is specifically expressed in neural crest tissues in Xenopus embryos and knockdown of XRFC by specific morpholino results in severe neurocristopathies. Inhibition of RFC blocked the expression of a series of neural crest marker genes while overexpression of RFC or injection of 5-methyltetrahydrofolate expanded the neural crest territories. In animal cap assays, knockdown of RFC dramatically reduced the mono- and trimethyl-Histone3-K4 levels and co-injection of the lysine methyltransferase hMLL1 largely rescued the XRFC morpholino phenotype. Our data revealed that the RFC mediated folate metabolic pathway likely potentiates neural crest gene expression through epigenetic modifications.

  2. Effect of Cryopreservation and Post-Cryopreservation Somatic Embryogenesis on the Epigenetic Fidelity of Cocoa (Theobroma cacao L.).

    Science.gov (United States)

    Adu-Gyamfi, Raphael; Wetten, Andy; Marcelino Rodríguez López, Carlos

    2016-01-01

    While cocoa plants regenerated from cryopreserved somatic embryos can demonstrate high levels of phenotypic variability, little is known about the sources of the observed variability. Previous studies have shown that the encapsulation-dehydration cryopreservation methodology imposes no significant extra mutational load since embryos carrying high levels of genetic variability are selected against during protracted culture. Also, the use of secondary rather than primary somatic embryos has been shown to further reduce the incidence of genetic somaclonal variation. Here, the effect of in vitro conservation, cryopreservation and post-cryopreservation generation of somatic embryos on the appearance of epigenetic somaclonal variation were comparatively assessed. To achieve this we compared the epigenetic profiles, generated using Methylation Sensitive Amplified Polymorphisms, of leaves collected from the ortet tree and from cocoa somatic embryos derived from three in vitro conditions: somatic embryos, somatic embryos cryopreserved in liquid nitrogen and somatic embryos generated from cryoproserved somatic embryos. Somatic embryos accumulated epigenetic changes but these were less extensive than in those regenerated after storage in LN. Furthermore, the passage of cryopreserved embryos through another embryogenic stage led to further increase in variation. Interestingly, this detected variability appears to be in some measure reversible. The outcome of this study indicates that the cryopreservation induced phenotypic variability could be, at least partially, due to DNA methylation changes. Phenotypic variability observed in cryostored cocoa somatic-embryos is epigenetic in nature. This variability is partially reversible, not stochastic in nature but a directed response to the in-vitro culture and cryopreservation.

  3. Epigenetic changes detected in micropropagated hop plants.

    Science.gov (United States)

    Peredo, Elena L; Arroyo-García, Rosa; Revilla, M Angeles

    2009-07-01

    Micropropagation is a widely used technique in hops (Humulus lupulus L.). However, to the best of our knowledge, the genetic and epigenetic stability of the microplants has never been tested before. In the present study, two hop accessions were established in vitro and micropropagated for 2 years. The genetic and epigenetic stability of the in vitro plants was analyzed with several molecular techniques: random amplified DNA polymorphism (RAPD), retrotransposon microsatellite amplified polymorphism (REMAP), and methylation-sensitive amplification polymorphism (MSAP). No genetic variation among control and treated plants was found, even after 12 cycles of micropropagation. Epigenetic variation was detected, first, when field and in vitro samples were compared. Nearly a 30% of the detected fragments presented the same pattern of alterations in all the vitroplants. Second, lower levels of epigenetic variation were detected among plants from the different subcultures. Part of this detected variation seemed to be accumulated along the 12 sequential subcultures tested.

  4. Epigenetics in radiotherapy: Where are we heading?

    International Nuclear Information System (INIS)

    Smits, Kim M.; Melotte, Veerle; Niessen, Hanneke E.C.; Dubois, Ludwig; Oberije, Cary; Troost, Esther G.C.; Starmans, Maud H.W.; Boutros, Paul C.; Vooijs, Marc; Engeland, Manon van; Lambin, Philippe

    2014-01-01

    Radiotherapy is an important component of anti-cancer treatment. However, not all cancer patients respond to radiotherapy, and with current knowledge clinicians are unable to predict which patients are at high risk of recurrence after radiotherapy. There is therefore an urgent need for biomarkers to guide clinical decision-making. Although the importance of epigenetic alterations is widely accepted, their application as biomarkers in radiotherapy has not been studied extensively. In addition, it has been suggested that radiotherapy itself introduces epigenetic alterations. As epigenetic alterations can potentially be reversed by drug treatment, they are interesting candidate targets for anticancer therapy or radiotherapy sensitizers. The application of demethylating drugs or histone deacetylase inhibitors to sensitize patients for radiotherapy has been studied in vitro, in vivo as well as in clinical trials with promising results. This review describes the current knowledge on epigenetics in radiotherapy

  5. The evolutionary implications of epigenetic inheritance.

    Science.gov (United States)

    Jablonka, Eva

    2017-10-06

    The Modern Evolutionary Synthesis (MS) forged in the mid-twentieth century was built on a notion of heredity that excluded soft inheritance, the inheritance of the effects of developmental modifications. However, the discovery of molecular mechanisms that generate random and developmentally induced epigenetic variations is leading to a broadening of the notion of biological heredity that has consequences for ideas about evolution. After presenting some old challenges to the MS that were raised, among others, by Karl Popper, I discuss recent research on epigenetic inheritance, which provides experimental and theoretical support for these challenges. There is now good evidence that epigenetic inheritance is ubiquitous and is involved in adaptive evolution and macroevolution. I argue that the many evolutionary consequences of epigenetic inheritance open up new research areas and require the extension of the evolutionary synthesis beyond the current neo-Darwinian model.

  6. Epigenetic Regulation in Prostate Cancer Progression.

    Science.gov (United States)

    Ruggero, Katia; Farran-Matas, Sonia; Martinez-Tebar, Adrian; Aytes, Alvaro

    2018-01-01

    An important number of newly identified molecular alterations in prostate cancer affect gene encoding master regulators of chromatin biology epigenetic regulation. This review will provide an updated view of the key epigenetic mechanisms underlying prostate cancer progression, therapy resistance, and potential actionable mechanisms and biomarkers. Key players in chromatin biology and epigenetic master regulators has been recently described to be crucially altered in metastatic CRPC and tumors that progress to AR independency. As such, epigenetic dysregulation represents a driving mechanism in the reprograming of prostate cancer cells as they lose AR-imposed identity. Chromatin integrity and accessibility for transcriptional regulation are key features altered in cancer progression, and particularly relevant in nuclear hormone receptor-driven tumors like prostate cancer. Understanding how chromatin remodeling dictates prostate development and how its deregulation contributes to prostate cancer onset and progression may improve risk stratification and treatment selection for prostate cancer patients.

  7. Epigenetic Regulation of Monocyte and Macrophage Function

    NARCIS (Netherlands)

    Hoeksema, Marten A.; de Winther, Menno P. J.

    2016-01-01

    Monocytes and macrophages are key players in tissue homeostasis and immune responses. Epigenetic processes tightly regulate cellular functioning in health and disease. Recent Advances: Recent technical developments have allowed detailed characterizations of the transcriptional circuitry underlying

  8. Epigenetics of dominance for enzyme activity

    Indian Academy of Sciences (India)

    Unknown

    dimer over a wide range of H+ concentrations accounts for the epigenetics of dominance for enzyme activity. [Trehan K S ... The present study has been carried on acid phosphatase .... enzyme activity over mid parent value (table 3, col. 13),.

  9. Dubbing SAGA unveils new epigenetic crosstalk.

    Science.gov (United States)

    Pijnappel, W W M Pim; Timmers, H Th Marc

    2008-02-01

    In a recent issue of Molecular Cell, two independent studies (Zhang et al., 2008; Zhao et al., 2008) provide compelling evidence that targeted deubiquitylation of histones is intimately linked to transcription activation, epigenetic regulation, and cancer progression.

  10. Epigenetic differences in monozygotic twins discordant for major depressive disorder.

    Science.gov (United States)

    Malki, K; Koritskaya, E; Harris, F; Bryson, K; Herbster, M; Tosto, M G

    2016-06-14

    Although monozygotic (MZ) twins share the majority of their genetic makeup, they can be phenotypically discordant on several traits and diseases. DNA methylation is an epigenetic mechanism that can be influenced by genetic, environmental and stochastic events and may have an important impact on individual variability. In this study we explored epigenetic differences in peripheral blood samples in three MZ twin studies on major depressive disorder (MDD). Epigenetic data for twin pairs were collected as part of a previous study using 8.1-K-CpG microarrays tagging DNA modification in white blood cells from MZ twins discordant for MDD. Data originated from three geographical regions: UK, Australia and the Netherlands. Ninety-seven MZ pairs (194 individuals) discordant for MDD were included. Different methods to address non independently-and-identically distributed (non-i.i.d.) data were evaluated. Machine-learning methods with feature selection centered on support vector machine and random forest were used to build a classifier to predict cases and controls based on epivariations. The most informative variants were mapped to genes and carried forward for network analysis. A mixture approach using principal component analysis (PCA) and Bayes methods allowed to combine the three studies and to leverage the increased predictive power provided by the larger sample. A machine-learning algorithm with feature reduction classified affected from non-affected twins above chance levels in an independent training-testing design. Network analysis revealed gene networks centered on the PPAR-γ (NR1C3) and C-MYC gene hubs interacting through the AP-1 (c-Jun) transcription factor. PPAR-γ (NR1C3) is a drug target for pioglitazone, which has been shown to reduce depression symptoms in patients with MDD. Using a data-driven approach we were able to overcome challenges of non-i.i.d. data when combining epigenetic studies from MZ twins discordant for MDD. Individually, the studies yielded

  11. Dynamic epigenetic responses to muscle contraction

    DEFF Research Database (Denmark)

    Rasmussen, Morten; Zierath, Juleen R; Barrès, Romain

    2014-01-01

    Skeletal muscle is a malleable organ that responds to a single acute exercise bout by inducing the expression of genes involved in structural, metabolic and functional adaptations. Several epigenetic mechanisms including histone H4 deacetylation and loss of promoter methylation have been implicated...... in modifying exercise-responsive gene expression. These transient changes suggest that epigenetic mechanisms are not restricted to early stages of human development but are broad dynamic controllers of genomic plasticity in response to environmental factors....

  12. Conference scene: Select Biosciences Epigenetics Europe 2010.

    Science.gov (United States)

    Razvi, Enal S

    2011-02-01

    The field of epigenetics is now on a geometric rise, driven in a large part by the realization that modifiers of chromatin are key regulators of biological processes in vivo. The three major classes of epigenetic effectors are DNA methylation, histone post-translational modifications (such as acetylation, methylation or phosphorylation) and small noncoding RNAs (most notably microRNAs). In this article, I report from Select Biosciences Epigenetics Europe 2010 industry conference held on 14-15 September 2010 at The Burlington Hotel, Dublin, Ireland. This industry conference was extremely well attended with a global pool of delegates representing the academic research community, biotechnology companies and pharmaceutical companies, as well as the technology/tool developers. This conference represented the current state of the epigenetics community with cancer/oncology as a key driver. In fact, it has been estimated that approximately 45% of epigenetic researchers today identify cancer/oncology as their main area of focus vis-à-vis their epigenetic research efforts.

  13. Development of a method for fabricating polypropylene non-articulated dorsiflexion assist ankle foot orthoses with predetermined stiffness.

    Science.gov (United States)

    Ramsey, Jason Allan

    2011-03-01

    A non-articulated plantarflexion resist ankle foot orthosis (AFO), commonly known as a posterior leaf spring AFO, is indicated for patients with motor impairment to the dorsiflexors. The AFO is often custom molded to a patient's lower limb anatomy and fabricated from polypropylene. There are no established guidelines for fabricating this type of AFO with predetermined stiffness of the ankle region for normal walking speeds. Therefore an AFO may not meet the biomechanical needs of the patient. Quantify the biomechanical ankle stiffness requirement for an individual with complete dorsiflexor impairment and develop a method for fabricating an AFO with ankle stiffness to meet that requirement. Experimental, bench research. The literature on sagittal biomechanics of non-pathological adults was reviewed to derive the stiffness of the ankle during loading response. Computer models of 144 AFOs were created with geometric variations to account for differences in human anthropometrics. Computer-based finite element analysis was employed to determine the stiffness and safety factor of the models. Stiffness of the AFOs ranged from 0.04 to 1.8 Nm/deg. This ample range is expected to account for the stiffness required for most adults with complete dorsiflexor impairment. At 5° deflection the factor of safety (ratio of strength to stress) ranged from 2.8 to 9.1. A computer program was generated that computes AFO stiffness from user-input variables of AFO geometry. The stiffness is compared to a theoretically appropriate stiffness based on the patient mass. The geometric variables can be modified until there is a close match, resulting in AFO design specification that is appropriate for the patient. Through validation on human subjects, this method may benefit patient outcomes in clinical practice by avoiding the current uncertainty surrounding AFO performance and reducing the labor and time involved in rectifying a custom AFO post-fabrication. This method provides an avenue for

  14. How physicians identify with predetermined personalities and links to perceived performance and wellness outcomes: a cross-sectional study.

    Science.gov (United States)

    Lemaire, Jane B; Wallace, Jean E

    2014-11-29

    Certain personalities are ascribed to physicians. This research aims to measure the extent to which physicians identify with three predetermined personalities (workaholic, Type A and control freak) and to explore links to perceptions of professional performance, and wellness outcomes. This is a cross-sectional study using a mail-out questionnaire sent to all practicing physicians (2957 eligible, 1178 responses, 40% response rate) in a geographical health region within a western Canadian province. Survey items were used to assess the extent to which participants felt they are somewhat of a workaholic, Type A and/or control freak, and if they believed that having these personalities makes one a better doctor. Participants' wellness outcomes were also measured. Zero-order correlations were used to determine the relationships between physicians identifying with a personality and feeling it makes one a better doctor. T-tests were used to compare measures of physician wellness for those who identified with the personality versus those who did not. 53% of participants identified with the workaholic personality, 62% with the Type A, and 36% with the control freak. Identifying with any one of the personalities was correlated with feeling it makes one a better physician. There were statistically significant differences in several wellness outcomes comparing participants who identified with the personalities versus those who did not. These included higher levels of emotional exhaustion (workaholic, Type A and control freak), higher levels of anxiety (Type A and control freak) and higher levels of depression, poorer mental health and lower levels of job satisfaction (control freak). Participants who identified with the workaholic personality versus those who did not reported higher levels of job satisfaction, rewarding patient experiences and career commitment. Most participants identified with at least one of the three personalities. The beliefs of some participants that

  15. Epigenetic variability in the genetically uniform forest tree species Pinus pinea L.

    Directory of Open Access Journals (Sweden)

    Enrique Sáez-Laguna

    Full Text Available There is an increasing interest in understanding the role of epigenetic variability in forest species and how it may contribute to their rapid adaptation to changing environments. In this study we have conducted a genome-wide analysis of cytosine methylation pattern in Pinus pinea, a species characterized by very low levels of genetic variation and a remarkable degree of phenotypic plasticity. DNA methylation profiles of different vegetatively propagated trees from representative natural Spanish populations of P. pinea were analyzed with the Methylation Sensitive Amplified Polymorphism (MSAP technique. A high degree of cytosine methylation was detected (64.36% of all scored DNA fragments. Furthermore, high levels of epigenetic variation were observed among the studied individuals. This high epigenetic variation found in P. pinea contrasted with the lack of genetic variation based on Amplified Fragment Length Polymorphism (AFLP data. In this manner, variable epigenetic markers clearly discriminate individuals and differentiates two well represented populations while the lack of genetic variation revealed with the AFLP markers fail to differentiate at both, individual or population levels. In addition, the use of different replicated trees allowed identifying common polymorphic methylation sensitive MSAP markers among replicates of a given propagated tree. This set of MSAPs allowed discrimination of the 70% of the analyzed trees.

  16. Epigenetic modulators of monocytic function: implication for steady state and disease in the CNS .

    Directory of Open Access Journals (Sweden)

    F. Nina Papavasiliou

    2016-01-01

    Full Text Available Epigenetic alterations are necessary for the establishment of functional and phenotypic diversity in populations of immune cells of the monocytic lineage. The epigenetic status of individual genes at different time points defines their transcriptional responses throughout development and in response to environmental stimuli. Epigenetic states are defined at the level of DNA modifications, chromatin modifications, as well as at the level of RNA base changes through RNA editing. Drawing from lessons regarding the epigenome and epitranscriptome of cells of the monocytic lineage in the periphery, and from recently published RNAseq data deriving from brain-resident monocytes, we discuss the impact of modulation of these epigenetic states and how they affect processes important for the development of a healthy brain, as well as mechanisms of neurodegenerative disease and aging. An understanding of the varied brain responses and pathologies in light of these novel gene regulatory systems in monocytes will lead to important new insights in the understanding of the aging process and the treatment and diagnosis of neurodegenerative disease.

  17. Interplay of Inflammatory Mediators with Epigenetics and Cartilage Modifications in Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Swarna Raman

    2018-03-01

    Full Text Available Osteoarthritis (OA, a degenerative disease of diarthrodial joints, is influenced by mechanical and inflammatory factors with aging, obesity, chronic injuries, and secondary diseases thought to be major factors driving the process of articular cartilage degeneration. Chondrocytes, the cellular component of cartilage, reside in an avascular environment and normally have limited potential to replicate. However, extrinsic factors such as injury to the joint or intrinsic alterations to the chondrocytes themselves can lead to an altered phenotype and development of OA. Synovial inflammation is also a pivotal element of the osteoarthritic, degenerative process: influx of pro-inflammatory cytokines and production of matrix metalloproteinases accelerate advanced cellular processes such as synovitis and cartilage damage. As well as a genetic input, recent data have highlighted epigenetic factors as contributing to disease. Studies conducted over the last decade have focused on three key aspects in OA; inflammation and the immune response, genome-wide association studies that have identified important genes undergoing epigenetic modifications, and finally how chondrocytes transform in their function during development and disease. Data highlighted here have identified critical inflammatory genes involved in OA and how these factors impact chondrocyte hypertrophy in the disease. This review also addresses key inflammatory factors in synovial inflammation, epigenetics, and chondrocyte fate, and how agents that inhibit epigenetic mechanisms like DNA methylation and histone modifications could aid in development of long-term treatment strategies for the disease.

  18. Epigenetic variability in the genetically uniform forest tree species Pinus pinea L.

    Science.gov (United States)

    Sáez-Laguna, Enrique; Guevara, María-Ángeles; Díaz, Luis-Manuel; Sánchez-Gómez, David; Collada, Carmen; Aranda, Ismael; Cervera, María-Teresa

    2014-01-01

    There is an increasing interest in understanding the role of epigenetic variability in forest species and how it may contribute to their rapid adaptation to changing environments. In this study we have conducted a genome-wide analysis of cytosine methylation pattern in Pinus pinea, a species characterized by very low levels of genetic variation and a remarkable degree of phenotypic plasticity. DNA methylation profiles of different vegetatively propagated trees from representative natural Spanish populations of P. pinea were analyzed with the Methylation Sensitive Amplified Polymorphism (MSAP) technique. A high degree of cytosine methylation was detected (64.36% of all scored DNA fragments). Furthermore, high levels of epigenetic variation were observed among the studied individuals. This high epigenetic variation found in P. pinea contrasted with the lack of genetic variation based on Amplified Fragment Length Polymorphism (AFLP) data. In this manner, variable epigenetic markers clearly discriminate individuals and differentiates two well represented populations while the lack of genetic variation revealed with the AFLP markers fail to differentiate at both, individual or population levels. In addition, the use of different replicated trees allowed identifying common polymorphic methylation sensitive MSAP markers among replicates of a given propagated tree. This set of MSAPs allowed discrimination of the 70% of the analyzed trees.

  19. Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: New strategies for toxicity testing?

    Science.gov (United States)

    Dusinska, Maria; Tulinska, Jana; El Yamani, Naouale; Kuricova, Miroslava; Liskova, Aurelia; Rollerova, Eva; Rundén-Pran, Elise; Smolkova, Bozena

    2017-11-01

    The unique properties of nanomaterials (NMs) are beneficial in numerous industrial and medical applications. However, they could also induce unintended effects. Thus, a proper strategy for toxicity testing is essential in human hazard and risk assessment. Toxicity can be tested in vivo and in vitro; in compliance with the 3Rs, alternative strategies for in vitro testing should be further developed for NMs. Robust, standardized methods are of great importance in nanotoxicology, with comprehensive material characterization and uptake as an integral part of the testing strategy. Oxidative stress has been shown to be an underlying mechanism of possible toxicity of NMs, causing both immunotoxicity and genotoxicity. For testing NMs in vitro, a battery of tests should be performed on cells of human origin, either cell lines or primary cells, in conditions as close as possible to an in vivo situation. Novel toxicity pathways, particularly epigenetic modification, should be assessed along with conventional toxicity testing methods. However, to initiate epigenetic toxicity screens for NM exposure, there is a need to better understand their adverse effects on the epigenome, to identify robust and reproducible causal links between exposure, epigenetic changes and adverse phenotypic endpoints, and to develop improved assays to monitor epigenetic toxicity. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Epigenetic Etiology of Intellectual Disability.

    Science.gov (United States)

    Iwase, Shigeki; Bérubé, Nathalie G; Zhou, Zhaolan; Kasri, Nael Nadif; Battaglioli, Elena; Scandaglia, Marilyn; Barco, Angel

    2017-11-08

    Intellectual disability (ID) is a prevailing neurodevelopmental condition associated with impaired cognitive and adaptive behaviors. Many chromatin-modifying enzymes and other epigenetic regulators have been genetically associated with ID disorders (IDDs). Here we review how alterations in the function of histone modifiers, chromatin remodelers, and methyl-DNA binding proteins contribute to neurodevelopmental defects and altered brain plasticity. We also discuss how progress in human genetics has led to the generation of mouse models that unveil the molecular etiology of ID, and outline the direction in which this field is moving to identify therapeutic strategies for IDDs. Importantly, because the chromatin regulators linked to IDDs often target common downstream genes and cellular processes, the impact of research in individual syndromes goes well beyond each syndrome and can also contribute to the understanding and therapy of other IDDs. Furthermore, the investigation of these disorders helps us to understand the role of chromatin regulators in brain development, plasticity, and gene expression, thereby answering fundamental questions in neurobiology. Copyright © 2017 the authors 0270-6474/17/3710773-10$15.00/0.

  1. Epigenetic regulation and fetal programming.

    Science.gov (United States)

    Gicquel, Christine; El-Osta, Assam; Le Bouc, Yves

    2008-02-01

    Fetal programming encompasses the role of developmental plasticity in response to environmental and nutritional signals during early life and its potential adverse consequences (risk of cardiovascular, metabolic and behavioural diseases) in later life. The first studies in this field highlighted an association between poor fetal growth and chronic adult diseases. However, environmental signals during early life may lead to adverse long-term effects independently of obvious effects on fetal growth. Adverse long-term effects reflect a mismatch between early (fetal and neonatal) environmental conditions and the conditions that the individual will confront later in life. The mechanisms underlying this risk remain unclear. However, experimental data in rodents and recent observations in humans suggest that epigenetic changes in regulatory genes and growth-related genes play a significant role in fetal programming. Improvements in our understanding of the biochemical and molecular mechanisms at play in fetal programming would make it possible to identify biomarkers for detecting infants at high risk of adult-onset diseases. Such improvements should also lead to the development of preventive and therapeutic strategies.

  2. Epigenetic approaches towards radiation countermeasure

    International Nuclear Information System (INIS)

    Agrawala, Paban K.

    2012-01-01

    In the recent years, histone deacetylase inhibitors (HDACi) have gained tremendous attention for their anticancer, tumor radiosensitising and chemosensitising properties. HDACi enhance the acetylation status of histone proteins of the chromatin besides other non-histone target proteins, an effect that is regulated by the HDACs (histone deacetylases) and HATs (histone acetyltransferases) in the cells. HDACi affect the cell cycle progression, differentiation, DNA damage and repair processes and cell death which contributes to their anticancer properties. One of the main reasons for HDACi gaining attention as potential anticancer therapeutics is their profound action on cancer cells with minimal or no effect on normal cells. However, in recent years, the possible non-oncological applications of HDACi are being explored extensively viz, in neurodegenerative diseases. Ionizing radiation exposure leads to significant alterations in signal transduction processes, changes gene expression patterns, affects DNA damage and repair processes, cell cycle progression and the underlying epigenetic changes (acetylation of histones and methylation of DNA and histones in particular) are now emerging. Some recent literatures suggest that HDACi can render cytoprotective properties in normal tissues. We at INMAS evaluated certain weak HDACi molecules of dietary origin for their ability to modulate cellular radiation in normal cells and animals. As per our expectations, post irradiation treatment with selected HDACi molecules rendered significant reduction in radiation induced damages. The possible mechanisms of action of HDACi in reducing radiation injuries with be discussed based on our won results and recent reports. (author)

  3. Epigenetic Regulation of the Oxytocin Receptor Gene: Implications for Behavioral Neuroscience

    Directory of Open Access Journals (Sweden)

    Robert eKumsta

    2013-05-01

    Full Text Available Genetic approaches have improved our understanding of the neurobiological basis of social behavior and cognition. For instance, common polymorphisms of genes involved in oxytocin signaling have been associated with sociobehavioral phenotypes in healthy samples as well as in subjects with mental disorders. More recently, attention has been drawn to epigenetic mechanisms, which regulate genetic function and expression without changes to the underlying DNA sequence. We provide an overview of the functional importance of oxytocin receptor gene (OXTR promoter methylation and summarize studies that have investigated the role of OXTR methylation in behavioral phenotypes. There is first evidence that OXTR methylation is associated with autism, high callous-unemotional traits, and differential activation of brain regions involved in social perception. Furthermore, psychosocial stress exposure might dynamically regulate OXTR. Given evidence that epigenetic states of genes can be modified by experiences, especially those occurring in sensitive periods early in development, we conclude with a discussion on the effects of traumatic experience on the developing oxytocin system. Epigenetic modification of genes involved in oxytocin signaling might be involved in the mechanisms mediating the long-term influence of early adverse experiences on socio-behavioral outcomes.

  4. 'Biologizing' Psychopathy: Ethical, Legal, and Research Implications at the Interface of Epigenetics and Chronic Antisocial Conduct.

    Science.gov (United States)

    Tamatea, Armon J

    2015-10-01

    Epigenetics, a field that links genetics and environmental influences on the expression of phenotypic traits, offers to increase our understanding of the development and trajectory of disease and psychological disorders beyond that thought of traditional genetic research and behavioural measures. By extension, this new perspective has implications for risk and risk management of antisocial behaviour where there is a biological component, such as psychopathy. Psychopathy is a personality disorder associated with repeat displays of antisocial behaviour, and is associated with the disproportionate imposition of harm on communities. Despite advances in our knowledge of psychopathic individuals, the construct remains complex and is hampered by a lack of integration across a range of fundamental domains. The clinical and forensic research on psychopathy is brought into conversation with the emerging field of epigenetics to highlight critical issues of (1) clinical definition and diagnosis, (2) assessment, (3) aetiology of psychopathic phenotypes, and (4) treatment and rehabilitation approaches. Broader ethical and legal questions of the role of epigenetic mechanisms in the management of psychopathy beyond the criminal justice arena are also outlined. Copyright © 2015 John Wiley & Sons, Ltd.

  5. Early-life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice.

    Science.gov (United States)

    Holland, Michelle L; Lowe, Robert; Caton, Paul W; Gemma, Carolina; Carbajosa, Guillermo; Danson, Amy F; Carpenter, Asha A M; Loche, Elena; Ozanne, Susan E; Rakyan, Vardhman K

    2016-07-29

    A suboptimal early-life environment, due to poor nutrition or stress during pregnancy, can influence lifelong phenotypes in the progeny. Epigenetic factors are thought to be key mediators of these effects. We show that protein restriction in mice from conception until weaning induces a linear correlation between growth restriction and DNA methylation at ribosomal DNA (rDNA). This epigenetic response remains into adulthood and is restricted to rDNA copies associated with a specific genetic variant within the promoter. Related effects are also found in models of maternal high-fat or obesogenic diets. Our work identifies environmentally induced epigenetic dynamics that are dependent on underlying genetic variation and establishes rDNA as a genomic target of nutritional insults. Copyright © 2016, American Association for the Advancement of Science.

  6. Aebp2 as an epigenetic regulator for neural crest cells.

    Directory of Open Access Journals (Sweden)

    Hana Kim

    Full Text Available Aebp2 is a potential targeting protein for the mammalian Polycomb Repression Complex 2 (PRC2. We generated a mutant mouse line disrupting the transcription of Aebp2 to investigate its in vivo roles. Aebp2-mutant homozygotes were embryonic lethal while heterozygotes survived to adulthood with fertility. In developing mouse embryos, Aebp2 is expressed mainly within cells of neural crest origin. In addition, many heterozygotes display a set of phenotypes, enlarged colon and hypopigmentation, similar to those observed in human patients with Hirschsprung's disease and Waardenburg syndrome. These phenotypes are usually caused by the absence of the neural crest-derived ganglia in hindguts and melanocytes. ChIP analyses demonstrated that the majority of the genes involved in the migration and development process of neural crest cells are downstream target genes of AEBP2 and PRC2. Furthermore, expression analyses confirmed that some of these genes are indeed affected in the Aebp2 heterozygotes. Taken together, these results suggest that Aebp2 may regulate the migration and development of the neural crest cells through the PRC2-mediated epigenetic mechanism.

  7. Epigenetic mechanism of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Niwa, Ohtsura

    1995-01-01

    Carcinogenic action of radiations has long been thought to be due to its mutagenic activity. Since DNA damage is induced and distributes in a stochastic fashion, radiation induction of cancers was also assumed to follow a stochastic kinetics. However, recent progress in radiation research has revealed that some features of radiation carcinogenesis are not explainable by the simple action of radiation as a DNA damaging and mutagenic agent. Firstly, frequencies of radiation-induced transformation in vitro and radiation-induced mammary cancers in rats are too high to be accounted for by the frequency of radiation-induced mutation. Secondly, trans-generation carcinogenesis among F1 mice born to irradiated parents occurs also much more frequently than to be predicted by the frequency of radiation induced germline mutation. Thirdly, multistage carcinogenesis theory predicts that carcinogens give hits to the target cells so as to shorten the latency of cancers. However, latencies of radiation induced solid cancers among atomic bomb survivors are similar to those of the control population. Fourthly, although radiation elevates the frequency of cancers, the induced cancers seem to share the same spectrum of cancer types as in the unirradiated control populations. This suggests that radiation induces cancer by enhancement of the spontaneous carcinogenesis process. These data suggest that the first step of radiation carcinogenesis may not be the direct induction of mutation. Radiation may induce genetic instability which increases the spontaneous mutation rate in the cells to produce carcinogenic mutations. Growth stimulatory effect of radiation may also contribute to the process. Thus, epigenetic, but not genetic effect of radiation might better contribute in the process of carcinogenesis. (author)

  8. Epigenetic Mechanisms of Depression and Antidepressants Action

    Science.gov (United States)

    Vialou, Vincent; Feng, Jian; Robison, Alfred J.; Nestler, Eric J.

    2013-01-01

    Epigenetic mechanisms, which control chromatin structure and function, mediate changes in gene expression that occur in response to diverse stimuli. Recent research has established that environmental events and behavioral experience induce epigenetic changes at particular gene loci that help shape neuronal plasticity and function, and hence behavior, and that some of these changes can be very stable and even persist for a lifetime. Increasing evidence supports the hypothesis that aberrations in chromatin remodeling and subsequent effects on gene expression within limbic brain regions contribute to the pathogenesis of depression and other stress-related disorders such as post-traumatic stress disorder and other anxiety syndromes. Likewise, the gradually developing but persistent therapeutic effects of antidepressant medications may be achieved in part via epigenetic mechanisms. This review discusses recent advances in understanding epigenetic regulation of stress-related disorders and focuses on three distinct aspects of stress-induced epigenetic pathology: the effects of stress and antidepressant treatment during adulthood, the life-long effects of early life stress on subsequent stress vulnerability, and the possible trans-generational transmission of stress-induced abnormalities. PMID:23020296

  9. Targeting Epigenetics to Prevent Obesity Promoted Cancers.

    Science.gov (United States)

    Berger, Nathan A; Scacheri, Peter C

    2018-03-01

    Epigenetic changes in DNA and associated chromatin proteins are increasingly being considered as important mediators of the linkage between obesity and cancer. Although multiple agents, targeted at epigenetic changes, are being tested for therapy of established cancers, this issue of Cancer Prevention Research carries two articles demonstrating that the bromodomain inhibitor I-BET-762 can attenuate adipose tissue-promoted cancers. Although I-BET-762 significantly delayed, rather than completely prevented, the onset of adiposity-promoted transformation and malignancy, these experiments provide important proof of principle for the strategies of targeting epigenetic changes to disrupt the obesity-cancer linkage. Because bromodomain proteins represent only one of multiple epigenetic mediators, it is probable that targeting other epigenetic processes, alone or in combination, may serve to even more effectively disrupt the obesity promotion of cancer. Given the magnitude of the current obesity pandemic and its impact on cancer, preventive measures to disrupt this linkage are critically important. Cancer Prev Res; 11(3); 125-8. ©2018 AACR See related article by Chakraborty et al., p. 129 . ©2018 American Association for Cancer Research.

  10. DNA-methylation profiling of fetal tissues reveals marked epigenetic differences between chorionic and amniotic samples.

    Directory of Open Access Journals (Sweden)

    Christel Eckmann-Scholz

    Full Text Available Epigenetic mechanisms including DNA methylation are supposed to play a key role in fetal development. Here we have investigated fetal DNA-methylation levels of 27,578 CpG loci in 47 chorionic villi (CVS and 16 amniotic cell (AC samples. Methylation levels differed significantly between karyotypically normal AC and CVS for 2,014 genes. AC showed more extreme DNA-methylation levels of these genes than CVS and the differentially methylated genes are significantly enriched for processes characteristic for the different cell types sampled. Furthermore, we identified 404 genes differentially methylated in CVS with trisomy 21. These genes were significantly enriched for high CG dinucleotid (CpG content and developmental processes associated with Down syndrome. Our study points to major tissue-specific differences of fetal DNA-methylation and gives rise to the hypothesis that part of the Down syndrome phenotype is epigenetically programmed in the first trimester of pregnancy.

  11. Toxoplasma gondii infection reduces predator aversion in rats through epigenetic modulation in the host medial amygdala.

    Science.gov (United States)

    Hari Dass, Shantala Arundhati; Vyas, Ajai

    2014-12-01

    Male rats (Rattus novergicus) infected with protozoan Toxoplasma gondii relinquish their innate aversion to the cat odours. This behavioural change is postulated to increase transmission of the parasite to its definitive felid hosts. Here, we show that the Toxoplasma gondii infection institutes an epigenetic change in the DNA methylation of the arginine vasopressin promoter in the medial amygdala of male rats. Infected animals exhibit hypomethylation of arginine vasopressin promoter, leading to greater expression of this nonapeptide. The infection also results in the greater activation of the vasopressinergic neurons after exposure to the cat odour. Furthermore, we show that loss of fear in the infected animals can be rescued by the systemic hypermethylation and recapitulated by directed hypomethylation in the medial amygdala. These results demonstrate an epigenetic proximate mechanism underlying the extended phenotype in the Rattus novergicus-Toxoplasma gondii association. © 2014 John Wiley & Sons Ltd.

  12. Genotype and phenotype in Klinefelter syndrome - impact of androgen receptor polymorphism and skewed X inactivation

    DEFF Research Database (Denmark)

    Bojesen, A; Hertz, J M; Gravholt, C H

    2011-01-01

    The phenotypic variation of Klinefelter syndrome (KS) is wide and may by caused by various genetic and epigenetic effects. Skewed inactivation of the supra-numerical X chromosome and polymorphism in the androgen receptor (AR) have been suggested as plausible causes. We wanted to describe X...

  13. Genome-Wide Locations of Potential Epimutations Associated with Environmentally Induced Epigenetic Transgenerational Inheritance of Disease Using a Sequential Machine Learning Prediction Approach

    OpenAIRE

    Haque, M. Muksitul; Holder, Lawrence B.; Skinner, Michael K.

    2015-01-01

    Environmentally induced epigenetic transgenerational inheritance of disease and phenotypic variation involves germline transmitted epimutations. The primary epimutations identified involve altered differential DNA methylation regions (DMRs). Different environmental toxicants have been shown to promote exposure (i.e., toxicant) specific signatures of germline epimutations. Analysis of genomic features associated with these epimutations identified low-density CpG regions (

  14. lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

    NARCIS (Netherlands)

    Wang, Zehua; Yang, Bo; Zhang, Min; Guo, Weiwei; Wu, Zhiyuan; Wang, Yue; Jia, Lin; Li, Song; Caesar-Johnson, Samantha J.; Demchok, John A.; Felau, Ina; Kasapi, Melpomeni; Ferguson, Martin L.; Hutter, Carolyn M.; Sofia, Heidi J.; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean C.; Zhang, Jiashan (Julia); Chudamani, Sudha; Liu, Jia; Lolla, Laxmi; Naresh, Rashi; Pihl, Todd; Sun, Qiang; Wan, Yunhu; Wu, Ye; Cho, Juok; DeFreitas, Timothy; Frazer, Scott; Gehlenborg, Nils; Getz, Gad; Heiman, David I.; Kim, Jaegil; Lawrence, Michael S.; Lin, Pei; Meier, Sam; Noble, Michael S.; Saksena, Gordon; Voet, Doug; Zhang, Hailei; Bernard, Brady; Chambwe, Nyasha; Dhankani, Varsha; Knijnenburg, Theo; Kramer, Roger; Leinonen, Kalle; Liu, Yuexin; Miller, Michael; Reynolds, Sheila; Shmulevich, Ilya; Thorsson, Vesteinn; Zhang, Wei; Akbani, Rehan; Broom, Bradley M.; Hegde, Apurva M.; Ju, Zhenlin; Kanchi, Rupa S.; Korkut, Anil; Li, Jun; Liang, Han; Ling, Shiyun; Liu, Wenbin; Lu, Yiling; Mills, Gordon B.; Ng, Kwok Shing; Rao, Arvind; Ryan, Michael; Wang, Jing; Weinstein, John N.; Zhang, Jiexin; Abeshouse, Adam; Armenia, Joshua; Chakravarty, Debyani; Chatila, Walid K.; Bruijn, Inode; Gao, Jianjiong; Gross, Benjamin E.; Heins, Zachary J.; Kundra, Ritika; La, Konnor; Ladanyi, Marc; Luna, Augustin; Nissan, Moriah G.; Ochoa, Angelica; Phillips, Sarah M.; Reznik, Ed; Sanchez-Vega, Francisco; Sander, Chris; Schultz, Nikolaus; Sheridan, Robert; Sumer, S. Onur; Sun, Yichao; Taylor, Barry S.; Wang, Jioajiao; Zhang, Hongxin; Anur, Pavana; Peto, Myron; Spellman, Paul; Benz, Christopher; Stuart, Joshua M.; Wong, Christopher K.; Yau, Christina; Hayes, D. Neil; Parker, Joel S.; Wilkerson, Matthew D.; Ally, Adrian; Balasundaram, Miruna; Bowlby, Reanne; Brooks, Denise; Carlsen, Rebecca; Chuah, Eric; Dhalla, Noreen; Holt, Robert; Jones, Steven J.M.; Kasaian, Katayoon; Lee, Darlene; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Mungall, Karen; Robertson, A. Gordon; Sadeghi, Sara; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Tse, Kane; Wong, Tina; Berger, Ashton C.; Beroukhim, Rameen; Cherniack, Andrew D.; Cibulskis, Carrie; Gabriel, Stacey B.; Gao, Galen F.; Ha, Gavin; Meyerson, Matthew; Schumacher, Steven E.; Shih, Juliann; Kucherlapati, Melanie H.; Kucherlapati, Raju S.; Baylin, Stephen; Cope, Leslie; Danilova, Ludmila; Bootwalla, Moiz S.; Lai, Phillip H.; Maglinte, Dennis T.; Van Den Berg, David J.; Weisenberger, Daniel J.; Auman, J. Todd; Balu, Saianand; Bodenheimer, Tom; Fan, Cheng; Hoadley, Katherine A.; Hoyle, Alan P.; Jefferys, Stuart R.; Jones, Corbin D.; Meng, Shaowu; Mieczkowski, Piotr A.; Mose, Lisle E.; Perou, Amy H.; Perou, Charles M.; Roach, Jeffrey; Shi, Yan; Simons, Janae V.; Skelly, Tara; Soloway, Matthew G.; Tan, Donghui; Veluvolu, Umadevi; Fan, Huihui; Hinoue, Toshinori; Laird, Peter W.; Shen, Hui; Zhou, Wanding; Bellair, Michelle; Chang, Kyle; Covington, Kyle; Creighton, Chad J.; Dinh, Huyen; Doddapaneni, Harsha Vardhan; Donehower, Lawrence A.; Drummond, Jennifer; Gibbs, Richard A.; Glenn, Robert; Hale, Walker; Han, Yi; Hu, Jianhong; Korchina, Viktoriya; Lee, Sandra; Lewis, Lora; Li, Wei; Liu, Xiuping; Morgan, Margaret; Morton, Donna; Muzny, Donna; Santibanez, Jireh; Sheth, Margi; Shinbrot, Eve; Wang, Linghua; Wang, Min; Wheeler, David A.; Xi, Liu; Zhao, Fengmei; Hess, Julian; Appelbaum, Elizabeth L.; Bailey, Matthew; Cordes, Matthew G.; Ding, Li; Fronick, Catrina C.; Fulton, Lucinda A.; Fulton, Robert S.; Kandoth, Cyriac; Mardis, Elaine R.; McLellan, Michael D.; Miller, Christopher A.; Schmidt, Heather K.; Wilson, Richard K.; Crain, Daniel; Curley, Erin; Gardner, Johanna; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Penny, Robert; Shelton, Candace; Shelton, Troy; Sherman, Mark; Thompson, Eric; Yena, Peggy; Bowen, Jay; Gastier-Foster, Julie M.; Gerken, Mark; Leraas, Kristen M.; Lichtenberg, Tara M.; Ramirez, Nilsa C.; Wise, Lisa; Zmuda, Erik; Corcoran, Niall; Costello, Tony; Hovens, Christopher; Carvalho, Andre L.; de Carvalho, Ana C.; Fregnani, José H.; Longatto-Filho, Adhemar; Reis, Rui M.; Scapulatempo-Neto, Cristovam; Silveira, Henrique C.S.; Vidal, Daniel O.; Burnette, Andrew; Eschbacher, Jennifer; Hermes, Beth; Noss, Ardene; Singh, Rosy; Anderson, Matthew L.; Castro, Patricia D.; Ittmann, Michael; Huntsman, David; Kohl, Bernard; Le, Xuan; Thorp, Richard; Andry, Chris; Duffy, Elizabeth R.; Lyadov, Vladimir; Paklina, Oxana; Setdikova, Galiya; Shabunin, Alexey; Tavobilov, Mikhail; McPherson, Christopher; Warnick, Ronald; Berkowitz, Ross; Cramer, Daniel; Feltmate, Colleen; Horowitz, Neil; Kibel, Adam; Muto, Michael; Raut, Chandrajit P.; Malykh, Andrei; Barnholtz-Sloan, Jill S.; Barrett, Wendi; Devine, Karen; Fulop, Jordonna; Ostrom, Quinn T.; Shimmel, Kristen; Wolinsky, Yingli; Sloan, Andrew E.; De Rose, Agostino; Giuliante, Felice; Goodman, Marc; Karlan, Beth Y.; Hagedorn, Curt H.; Eckman, John; Harr, Jodi; Myers, Jerome; Tucker, Kelinda; Zach, Leigh Anne; Deyarmin, Brenda; Hu, Hai; Kvecher, Leonid; Larson, Caroline; Mural, Richard J.; Somiari, Stella; Vicha, Ales; Zelinka, Tomas; Bennett, Joseph; Iacocca, Mary; Rabeno, Brenda; Swanson, Patricia; Latour, Mathieu; Lacombe, Louis; Têtu, Bernard; Bergeron, Alain; McGraw, Mary; Staugaitis, Susan M.; Chabot, John; Hibshoosh, Hanina; Sepulveda, Antonia; Su, Tao; Wang, Timothy; Potapova, Olga; Voronina, Olga; Desjardins, Laurence; Mariani, Odette; Roman-Roman, Sergio; Sastre, Xavier; Stern, Marc Henri; Cheng, Feixiong; Signoretti, Sabina; Berchuck, Andrew; Bigner, Darell; Lipp, Eric; Marks, Jeffrey; McCall, Shannon; McLendon, Roger; Secord, Angeles; Sharp, Alexis; Behera, Madhusmita; Brat, Daniel J.; Chen, Amy; Delman, Keith; Force, Seth; Khuri, Fadlo; Magliocca, Kelly; Maithel, Shishir; Olson, Jeffrey J.; Owonikoko, Taofeek; Pickens, Alan; Ramalingam, Suresh; Shin, Dong M.; Sica, Gabriel; Van Meir, Erwin G.; Zhang, Hongzheng; Eijckenboom, Wil; Gillis, Ad; Korpershoek, Esther; Looijenga, Leendert; Oosterhuis, Wolter; Stoop, Hans; van Kessel, Kim E.; Zwarthoff, Ellen C.; Calatozzolo, Chiara; Cuppini, Lucia; Cuzzubbo, Stefania; DiMeco, Francesco; Finocchiaro, Gaetano; Mattei, Luca; Perin, Alessandro; Pollo, Bianca; Chen, Chu; Houck, John; Lohavanichbutr, Pawadee; Hartmann, Arndt; Stoehr, Christine; Stoehr, Robert; Taubert, Helge; Wach, Sven; Wullich, Bernd; Kycler, Witold; Murawa, Dawid; Wiznerowicz, Maciej; Chung, Ki; Edenfield, W. Jeffrey; Martin, Julie; Baudin, Eric; Bubley, Glenn; Bueno, Raphael; De Rienzo, Assunta; Richards, William G.; Kalkanis, Steven; Mikkelsen, Tom; Noushmehr, Houtan; Scarpace, Lisa; Girard, Nicolas; Aymerich, Marta; Campo, Elias; Giné, Eva; Guillermo, Armando López; Van Bang, Nguyen; Hanh, Phan Thi; Phu, Bui Duc; Tang, Yufang; Colman, Howard; Evason, Kimberley; Dottino, Peter R.; Martignetti, John A.; Gabra, Hani; Juhl, Hartmut; Akeredolu, Teniola; Stepa, Serghei; Hoon, Dave; Ahn, Keunsoo; Kang, Koo Jeong; Beuschlein, Felix; Breggia, Anne; Birrer, Michael; Bell, Debra; Borad, Mitesh; Bryce, Alan H.; Castle, Erik; Chandan, Vishal; Cheville, John; Copland, John A.; Farnell, Michael; Flotte, Thomas; Giama, Nasra; Ho, Thai; Kendrick, Michael; Kocher, Jean Pierre; Kopp, Karla; Moser, Catherine; Nagorney, David; O'Brien, Daniel; O'Neill, Brian Patrick; Patel, Tushar; Petersen, Gloria; Que, Florencia; Rivera, Michael; Roberts, Lewis; Smallridge, Robert; Smyrk, Thomas; Stanton, Melissa; Thompson, R. Houston; Torbenson, Michael; Yang, Ju Dong; Zhang, Lizhi; Brimo, Fadi; Ajani, Jaffer A.; Gonzalez, Ana Maria Angulo; Behrens, Carmen; Bondaruk, Jolanta; Broaddus, Russell; Czerniak, Bogdan; Esmaeli, Bita; Fujimoto, Junya; Gershenwald, Jeffrey; Guo, Charles; Lazar, Alexander J.; Logothetis, Christopher; Meric-Bernstam, Funda; Moran, Cesar; Ramondetta, Lois; Rice, David; Sood, Anil; Tamboli, Pheroze; Thompson, Timothy; Troncoso, Patricia; Tsao, Anne; Wistuba, Ignacio; Carter, Candace; Haydu, Lauren; Hersey, Peter; Jakrot, Valerie; Kakavand, Hojabr; Kefford, Richard; Lee, Kenneth; Long, Georgina; Mann, Graham; Quinn, Michael; Saw, Robyn; Scolyer, Richard; Shannon, Kerwin; Spillane, Andrew; Stretch, Jonathan; Synott, Maria; Thompson, John; Wilmott, James; Al-Ahmadie, Hikmat; Chan, Timothy A.; Ghossein, Ronald; Gopalan, Anuradha; Levine, Douglas A.; Reuter, Victor; Singer, Samuel; Singh, Bhuvanesh; Tien, Nguyen Viet; Broudy, Thomas; Mirsaidi, Cyrus; Nair, Praveen; Drwiega, Paul; Miller, Judy; Smith, Jennifer; Zaren, Howard; Park, Joong Won; Hung, Nguyen Phi; Kebebew, Electron; Linehan, W. Marston; Metwalli, Adam R.; Pacak, Karel; Pinto, Peter A.; Schiffman, Mark; Schmidt, Laura S.; Vocke, Cathy D.; Wentzensen, Nicolas; Worrell, Robert; Yang, Hannah; Moncrieff, Marc; Goparaju, Chandra; Melamed, Jonathan; Pass, Harvey; Botnariuc, Natalia; Caraman, Irina; Cernat, Mircea; Chemencedji, Inga; Clipca, Adrian; Doruc, Serghei; Gorincioi, Ghenadie; Mura, Sergiu; Pirtac, Maria; Stancul, Irina; Tcaciuc, Diana; Albert, Monique; Alexopoulou, Iakovina; Arnaout, Angel; Bartlett, John; Engel, Jay; Gilbert, Sebastien; Parfitt, Jeremy; Sekhon, Harman; Thomas, George; Rassl, Doris M.; Rintoul, Robert C.; Bifulco, Carlo; Tamakawa, Raina; Urba, Walter; Hayward, Nicholas; Timmers, Henri; Antenucci, Anna; Facciolo, Francesco; Grazi, Gianluca; Marino, Mirella; Merola, Roberta; de Krijger, Ronald; Gimenez-Roqueplo, Anne Paule; Piché, Alain; Chevalier, Simone; McKercher, Ginette; Birsoy, Kivanc; Barnett, Gene; Brewer, Cathy; Farver, Carol; Naska, Theresa; Pennell, Nathan A.; Raymond, Daniel; Schilero, Cathy; Smolenski, Kathy; Williams, Felicia; Morrison, Carl; Borgia, Jeffrey A.; Liptay, Michael J.; Pool, Mark; Seder, Christopher W.; Junker, Kerstin; Omberg, Larsson; Dinkin, Mikhail; Manikhas, George; Alvaro, Domenico; Bragazzi, Maria Consiglia; Cardinale, Vincenzo; Carpino, Guido; Gaudio, Eugenio; Chesla, David; Cottingham, Sandra; Dubina, Michael; Moiseenko, Fedor; Dhanasekaran, Renumathy; Becker, Karl Friedrich; Janssen, Klaus Peter; Slotta-Huspenina, Julia; Abdel-Rahman, Mohamed H.; Aziz, Dina; Bell, Sue; Cebulla, Colleen M.; Davis, Amy; Duell, Rebecca; Elder, J. Bradley; Hilty, Joe; Kumar, Bahavna; Lang, James; Lehman, Norman L.; Mandt, Randy; Nguyen, Phuong; Pilarski, Robert; Rai, Karan; Schoenfield, Lynn; Senecal, Kelly; Wakely, Paul; Hansen, Paul; Lechan, Ronald; Powers, James; Tischler, Arthur; Grizzle, William E.; Sexton, Katherine C.; Kastl, Alison; Henderson, Joel; Porten, Sima; Waldmann, Jens; Fassnacht, Martin; Asa, Sylvia L.; Schadendorf, Dirk; Couce, Marta; Graefen, Markus; Huland, Hartwig; Sauter, Guido; Schlomm, Thorsten; Simon, Ronald; Tennstedt, Pierre; Olabode, Oluwole; Nelson, Mark; Bathe, Oliver; Carroll, Peter R.; Chan, June M.; Disaia, Philip; Glenn, Pat; Kelley, Robin K.; Landen, Charles N.; Phillips, Joanna; Prados, Michael; Simko, Jeffry; Smith-McCune, Karen; VandenBerg, Scott; Roggin, Kevin; Fehrenbach, Ashley; Kendler, Ady; Sifri, Suzanne; Steele, Ruth; Jimeno, Antonio; Carey, Francis; Forgie, Ian; Mannelli, Massimo; Carney, Michael; Hernandez, Brenda; Campos, Benito; Herold-Mende, Christel; Jungk, Christin; Unterberg, Andreas; von Deimling, Andreas; Bossler, Aaron; Galbraith, Joseph; Jacobus, Laura; Knudson, Michael; Knutson, Tina; Ma, Deqin; Milhem, Mohammed; Sigmund, Rita; Godwin, Andrew K.; Madan, Rashna; Rosenthal, Howard G.; Adebamowo, Clement; Adebamowo, Sally N.; Boussioutas, Alex; Beer, David; Giordano, Thomas; Mes-Masson, Anne Marie; Saad, Fred; Bocklage, Therese; Landrum, Lisa; Mannel, Robert; Moore, Kathleen; Moxley, Katherine; Postier, Russel; Walker, Joan; Zuna, Rosemary; Feldman, Michael; Valdivieso, Federico; Dhir, Rajiv; Luketich, James; Pinero, Edna M.Mora; Quintero-Aguilo, Mario; Carlotti, Carlos Gilberto; Dos Santos, Jose Sebastião; Kemp, Rafael; Sankarankuty, Ajith; Tirapelli, Daniela; Catto, James; Agnew, Kathy; Swisher, Elizabeth; Creaney, Jenette; Robinson, Bruce; Shelley, Carl Simon; Godwin, Eryn M.; Kendall, Sara; Shipman, Cassaundra; Bradford, Carol; Carey, Thomas; Haddad, Andrea; Moyer, Jeffey; Peterson, Lisa; Prince, Mark; Rozek, Laura; Wolf, Gregory; Bowman, Rayleen; Fong, Kwun M.; Yang, Ian; Korst, Robert; Rathmell, W. Kimryn; Fantacone-Campbell, J. Leigh; Hooke, Jeffrey A.; Kovatich, Albert J.; Shriver, Craig D.; DiPersio, John; Drake, Bettina; Govindan, Ramaswamy; Heath, Sharon; Ley, Timothy; Van Tine, Brian; Westervelt, Peter; Rubin, Mark A.; Lee, Jung Il; Aredes, Natália D.; Mariamidze, Armaz; Xie, Wen; Yang, Da

    2018-01-01

    We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1

  15. The expanding role of epigenetics in the development, diagnosis and treatment of prostate cancer and benign prostatic hyperplasia.

    Science.gov (United States)

    Dobosy, Joseph R; Roberts, J Lea W; Fu, Vivian X; Jarrard, David F

    2007-03-01

    Prostate cancer research has focused significant attention on the mutation, deletion or amplification of the DNA base sequence that encodes critical growth or suppressor genes. However, these changes have left significant gaps in our understanding of the development and progression of disease. It has become clear that epigenetic changes or modifications that influence phenotype without altering the genotype present a new and entirely different mechanism for gene regulation. Several interrelated epigenetic modifications that are altered in abnormal growth states are DNA methylation changes, histone modifications and genomic imprinting. We discuss the status of epigenetic alterations in prostate cancer and benign prostatic hyperplasia progression. In addition, the rationale and status of ongoing clinical trials altering epigenetic processes in urological diseases are reviewed. An online search of current and past peer reviewed literature on DNA methylation, histone acetylation and methylation, imprinting and epigenetics in prostate cancer and benign prostatic hyperplasia was performed. Relevant articles and reviews were examined and a synopsis of reproducible data was generated with the goal of informing the practicing urologist of these advances and their implications. Only 20 years ago the first study was published demonstrating global changes in DNA methylation patterns in tumors. Accumulating data have now identified specific genes that are commonly hypermethylated and inactivated during prostate cancer progression, including GSTpi, APC, MDR1, GPX3 and 14-3-3sigma. Altered histone modifications, including acetylation and methylation, were also recently described that may modify gene function, including androgen receptor function. These epigenetic changes are now being used to assist in prostate cancer diagnosis and cancer outcome prediction. Epigenetic changes appear to have a role in benign prostatic hyperplasia development as well as in the susceptibility of

  16. Epigenetic variation, inheritance, and parent-of-origin effects of cytosine methylation in maize (Zea mays).

    Science.gov (United States)

    Lauria, Massimiliano; Piccinini, Sara; Pirona, Raul; Lund, Gertrud; Viotti, Angelo; Motto, Mario

    2014-03-01

    Pure epigenetic variation, or epigenetic variation that is independent of genetic context, may provide a mechanism for phenotypic variation in the absence of DNA mutations. To estimate the extent of pure epigenetic variation within and across generations and to identify the DNA regions targeted, a group of eight plants derived from a highly inbred line of maize (Zea mays) was analyzed by the methylation-sensitive amplified polymorphism (MSAP) technique. We found that cytosine methylation (mC) differences among individuals accounted for up to 7.4% of CCGG sites investigated by MSAP. Of the differentially methylated fragments (DMFs) identified in the S0 generation, ∼12% were meiotically inherited for at least six generations. We show that meiotically heritable mC variation was consistently generated for an average of 0.5% CCGG sites per generation and that it largely occurred somatically. We provide evidence that mC variation can be established and inherited in a parent-of-origin manner, given that the paternal lineage is more prone to both forward and reverse mC changes. The molecular characterization of selected DMFs revealed that the variation was largely determined by CG methylation changes that map within gene regions. The expression analysis of genes overlapping with DMFs did not reveal an obvious correlation between mC variation and transcription, reinforcing the idea that the primary function of gene-body methylation is not to control gene expression. Because this study focuses on epigenetic variation in field-grown plants, the data presented herein pertain to spontaneous epigenetic changes of the maize genome in a natural context.

  17. Ancestral TCDD exposure promotes epigenetic transgenerational inheritance of imprinted gene Igf2: Methylation status and DNMTs

    International Nuclear Information System (INIS)

    Ma, Jing; Chen, Xi; Liu, Yanan; Xie, Qunhui; Sun, Yawen; Chen, Jingshan; Leng, Ling; Yan, Huan; Zhao, Bin; Tang, Naijun

    2015-01-01

    Ancestral TCDD exposure could induce epigenetic transgenerational phenotypes, which may be mediated in part by imprinted gene inheritance. The aim of our study was to evaluate the transgenerational effects of ancestral TCDD exposure on the imprinted gene insulin-like growth factor-2 (Igf2) in rat somatic tissue. TCDD was administered daily by oral gavage to groups of F0 pregnant SD rats at dose levels of 0 (control), 200 or 800 ng/kg bw during gestation day 8–14. Animal transgenerational model of ancestral exposure to TCDD was carefully built, avoiding sibling inbreeding. Hepatic Igf2 expression of the TCDD male progeny was decreased concomitantly with hepatic damage and increased activities of serum hepatic enzymes both in the F1 and F3 generation. Imprinted Control Region (ICR) of Igf2 manifested a hypermethylated pattern, whereas methylation status in the Differentially Methylated Region 2 (DMR2) showed a hypomethylated manner in the F1 generation. These epigenetic alterations in these two regions maintained similar trends in the F3 generation. Meanwhile, the expressions of DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) changed in a non-monotonic manner both in the F1 and F3 generation. This study provides evidence that ancestral TCDD exposure may promote epigenetic transgenerational alterations of imprinted gene Igf2 in adult somatic tissue. - Highlights: • Ancestral TCDD exposure induces epigenetic transgenerational inheritance. • Ancestral TCDD exposure affects methylation status in ICR and DMR2 region of Igf2. • DNMTs play a role in TCDD induced epigenetic transgenerational changes of Igf2.

  18. Genetic and epigenetic variants influencing the development of nonalcoholic fatty liver disease.

    Science.gov (United States)

    Li, Yu-Yuan

    2012-12-07

    Nonalcoholic fatty liver disease (NAFLD) is common worldwide. The importance of genetic and epigenetic changes in etiology and pathogenesis of NAFLD has been increasingly recognized. However, the exact mechanism is largely unknown. A large number of single nucleotide polymorphisms (SNPs) related to NAFLD has been documented by candidate gene studies (CGSs). Among these genes, peroxisome proliferatoractivated receptor-γ, adiponectin, leptin and tumor necrosis factor-α were frequently reported. Since the introduction of genome-wide association studies (GWASs), there have been significant advances in our understanding of genomic variations of NAFLD. Patatin-like phospholipase domain containing family member A3 (PNPLA3, SNP rs738409, encoding I148M), also termed adiponutrin, has caught most attention. The evidence that PNPLA3 is associated with increased hepatic fat levels and hepatic inflammation has been validated by a series of studies. Epigenetic modification refers to phenotypic changes caused by an adaptive mechanism unrelated to alteration of primary DNA sequences. Epigenetic regulation mainly includes microRNAs (miRs), DNA methylation, histone modifications and ubiquitination, among which miRs are studied most extensively. miRs are small natural single stranded RNA molecules regulating mRNA degradation or translation inhibition, subsequently altering protein expression of target genes. The miR-122, a highly abundant miR accounting for nearly 70% of all miRs in the liver, is significantly under-expressed in NAFLD subjects. Inhibition of miR-122 with an antisense oligonucleotide results in decreased mRNA expression of lipogenic genes and improvement of liver steatosis. The investigation into epigenetic involvement in NAFLD pathogenesis is just at the beginning and needs to be refined. This review summarizes the roles of genetics and epigenetics in the development of NAFLD. The progress made in this field may provide novel diagnostic biomarkers and therapeutic

  19. Epigenetic mediated transcriptional activation of WNT5A participates in arsenical-associated malignant transformation

    International Nuclear Information System (INIS)

    Jensen, Taylor J.; Wozniak, Ryan J.; Eblin, Kylee E.; Wnek, Sean M.; Gandolfi, A. Jay; Futscher, Bernard W.

    2009-01-01

    Arsenic is a human carcinogen with exposure associated with cancer of the lung, skin, and bladder. Many potential mechanisms have been implicated as playing a role in the process of arsenical-induced malignancy including the perturbation of signaling pathways and aberrant epigenetic regulation. We initiated studies to examine the role of a member of the non-canonical WNT signaling pathway, WNT5A, in UROtsa cells and arsenite [URO-ASSC] and monomethylarsonous acid [URO-MSC] malignantly transformed variants. We present data herein that suggest that WNT5A is transcriptionally activated during arsenical-induced malignant transformation. This WNT5A transcriptional activation is correlated with the enrichment of permissive histone modifications and the reduction of repressive modifications in the WNT5A promoter region. The epigenetic activation of WNT5A expression and acetylation of its promoter remain after the removal of the arsenical, consistent with the maintenance of an anchorage independent growth phenotype in these cells. Additionally, treatment with epigenetic modifying drugs supports a functional role for these epigenetic marks in controlling gene expression. Reduction of WNT5A using lentiviral shRNA greatly attenuated the ability of these cells to grow in an anchorage independent fashion. Extension of our model into human bladder cancer cell lines indicates that each of the cell lines examined also express WNT5A. Taken together, these data suggest that the epigenetic remodeling of the WNT5A promoter is correlated with its transcriptional activation and this upregulation likely participates in arsenical-induced malignant transformation

  20. Ancestral TCDD exposure promotes epigenetic transgenerational inheritance of imprinted gene Igf2: Methylation status and DNMTs

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Jing; Chen, Xi; Liu, Yanan [Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin 300070 (China); Xie, Qunhui [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Sun, Yawen; Chen, Jingshan; Leng, Ling; Yan, Huan [Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin 300070 (China); Zhao, Bin, E-mail: binzhao@rcees.ac.cn [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Tang, Naijun, E-mail: tangnaijun@tijmu.edu.cn [Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin 300070 (China)

    2015-12-01

    Ancestral TCDD exposure could induce epigenetic transgenerational phenotypes, which may be mediated in part by imprinted gene inheritance. The aim of our study was to evaluate the transgenerational effects of ancestral TCDD exposure on the imprinted gene insulin-like growth factor-2 (Igf2) in rat somatic tissue. TCDD was administered daily by oral gavage to groups of F0 pregnant SD rats at dose levels of 0 (control), 200 or 800 ng/kg bw during gestation day 8–14. Animal transgenerational model of ancestral exposure to TCDD was carefully built, avoiding sibling inbreeding. Hepatic Igf2 expression of the TCDD male progeny was decreased concomitantly with hepatic damage and increased activities of serum hepatic enzymes both in the F1 and F3 generation. Imprinted Control Region (ICR) of Igf2 manifested a hypermethylated pattern, whereas methylation status in the Differentially Methylated Region 2 (DMR2) showed a hypomethylated manner in the F1 generation. These epigenetic alterations in these two regions maintained similar trends in the F3 generation. Meanwhile, the expressions of DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) changed in a non-monotonic manner both in the F1 and F3 generation. This study provides evidence that ancestral TCDD exposure may promote epigenetic transgenerational alterations of imprinted gene Igf2 in adult somatic tissue. - Highlights: • Ancestral TCDD exposure induces epigenetic transgenerational inheritance. • Ancestral TCDD exposure affects methylation status in ICR and DMR2 region of Igf2. • DNMTs play a role in TCDD induced epigenetic transgenerational changes of Igf2.

  1. Three epigenetic information channels and their different roles in evolution

    NARCIS (Netherlands)

    Shea, N.; Pen, I.; Uller, T.

    There is increasing evidence for epigenetically mediated transgenerational inheritance across taxa. However, the evolutionary implications of such alternative mechanisms of inheritance remain unclear. Herein, we show that epigenetic mechanisms can serve two fundamentally different functions in

  2. Computer-Aided Drug Design in Epigenetics

    Directory of Open Access Journals (Sweden)

    Wenchao Lu

    2018-03-01

    Full Text Available Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field.

  3. Computer-Aided Drug Design in Epigenetics

    Science.gov (United States)

    Lu, Wenchao; Zhang, Rukang; Jiang, Hao; Zhang, Huimin; Luo, Cheng

    2018-01-01

    Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field. PMID:29594101

  4. Design of small molecule epigenetic modulators.

    Science.gov (United States)

    Pachaiyappan, Boobalan; Woster, Patrick M

    2014-01-01

    The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be categorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Epigenetic drift in the aging genome

    DEFF Research Database (Denmark)

    Tan, Qihua; Heijmans, Bastiaan T; Hjelmborg, Jacob V B

    2016-01-01

    for 10 years (age at intake 73-82 years). Biological pathway analysis and survival analysis were also conducted on CpGs showing longitudinal change in their DNA-methylation levels. Classical twin models were fitted to each CpG site to estimate the genetic and environmental effects on DNA...... × 10-07. Pathway analysis of genes linked to these CpGs identified biologically meaningful gene-sets involved in cellular-signalling events and in transmission across chemical synapses, which are important molecular underpinnings of aging-related degenerative disorders. CONCLUSION: Our epigenome......BACKGROUND: Current epigenetic studies on aging are dominated by the cross-sectional design that correlates subjects' ages or age groups with their measured epigenetic profiles. Such studies have been more aimed at age prediction or building up the epigenetic clock of age rather than focusing...

  6. Exploiting Epigenetic Alterations in Prostate Cancer.

    Science.gov (United States)

    Baumgart, Simon J; Haendler, Bernard

    2017-05-09

    Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.

  7. Exploiting Epigenetic Alterations in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Simon J. Baumgart

    2017-05-01

    Full Text Available Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.

  8. Diagnostic and prognostic epigenetic biomarkers in cancer.

    Science.gov (United States)

    Costa-Pinheiro, Pedro; Montezuma, Diana; Henrique, Rui; Jerónimo, Carmen

    2015-01-01

    Growing cancer incidence and mortality worldwide demands development of accurate biomarkers to perfect detection, diagnosis, prognostication and monitoring. Urologic (prostate, bladder, kidney), lung, breast and colorectal cancers are the most common and despite major advances in their characterization, this has seldom translated into biomarkers amenable for clinical practice. Epigenetic alterations are innovative cancer biomarkers owing to stability, frequency, reversibility and accessibility in body fluids, entailing great potential of assay development to assist in patient management. Several studies identified putative epigenetic cancer biomarkers, some of which have been commercialized. However, large multicenter validation studies are required to foster translation to the clinics. Herein we review the most promising epigenetic detection, diagnostic, prognostic and predictive biomarkers for the most common cancers.

  9. MicroRNAs, epigenetics and disease

    DEFF Research Database (Denmark)

    Silahtaroglu, Asli; Stenvang, Jan

    2010-01-01

    Epigenetics is defined as the heritable chances that affect gene expression without changing the DNA sequence. Epigenetic regulation of gene expression can be through different mechanisms such as DNA methylation, histone modifications and nucleosome positioning. MicroRNAs are short RNA molecules...... which do not code for a protein but have a role in post-transcriptional silencing of multiple target genes by binding to their 3' UTRs (untranslated regions). Both epigenetic mechanisms, such as DNA methylation and histone modifications, and the microRNAs are crucial for normal differentiation...... diseases. In the present chapter we will mainly focus on microRNAs and methylation and their implications in human disease, mainly in cancer....

  10. Interactions between epigenetics and metabolism in cancers

    International Nuclear Information System (INIS)

    Yun, Jihye; Johnson, Jared L.; Hanigan, Christin L.; Locasale, Jason W.

    2012-01-01

    Cancer progression is accompanied by widespread transcriptional changes and metabolic alterations. While it is widely accepted that the origin of cancer can be traced to the mutations that accumulate over time, relatively recent evidence favors a similarly fundamental role for alterations in the epigenome during tumorigenesis. Changes in epigenetics that arise from post-translational modifications of histones and DNA are exploited by cancer cells to upregulate and/or downregulate the expression levels of oncogenes and tumor suppressors, respectively. Although the mechanisms behind these modifications, in particular how they lead to gene silencing and activation, are still being understood, most of the enzymatic machinery of epigenetics require metabolites as substrates or cofactors. As a result, their activities can be influenced by the metabolic state of the cell. The purpose of this review is to give an overview of cancer epigenetics and metabolism and provide examples of where they converge.

  11. First Barcelona Conference on Epigenetics and Cancer

    Science.gov (United States)

    Palau, Anna; Perucho, Manuel; Esteller, Manel; Buschbeck, Marcus

    2014-01-01

    The Barcelona Conference on Epigenetics and Cancer (BCEC) entitled “Challenges, opportunities and perspectives” took place November 21–22, 2013 in Barcelona. The 2013 BCEC is the first edition of a series of annual conferences jointly organized by five leading research centers in Barcelona. These centers are the Institute of Predictive and Personalized Medicine of Cancer (IMPPC), the Biomedical Campus Bellvitge with its Program of Epigenetics and Cancer Biology (PEBC), the Centre for Genomic Regulation (CRG), the Institute for Biomedical Research (IRB), and the Molecular Biology Institute of Barcelona (IBMB). Manuel Perucho and Marcus Buschbeck from the Institute of Predictive and Personalized Medicine of Cancer put together the scientific program of the first conference broadly covering all aspects of epigenetic research ranging from fundamental molecular research to drug and biomarker development and clinical application. In one and a half days, 23 talks and 50 posters were presented to a completely booked out audience counting 270 participants. PMID:24413145

  12. Computer-Aided Drug Design in Epigenetics

    Science.gov (United States)

    Lu, Wenchao; Zhang, Rukang; Jiang, Hao; Zhang, Huimin; Luo, Cheng

    2018-03-01

    Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field.

  13. Interactions between epigenetics and metabolism in cancers

    Directory of Open Access Journals (Sweden)

    Jihye eYun

    2012-11-01

    Full Text Available Cancer progression is accompanied by widespread transcriptional changes and metabolic alterations. Although it is widely accepted that the origin of cancer can be traced to the mutations that accumulate over time, relatively recent evidence favors a similarly fundamental role for alterations in the epigenome during tumorigenesis. Changes in epigenetics that arise from post-translational modifications of histones and DNA, are exploited by cancer cells to upregulate and/or downregulate the expression levels of oncogenes and tumor suppressors, respectively. Although the mechanisms behind these modifications, in particular how they lead to gene silencing and activation, are still being understood, many enzymes that carry out post-translational modifications that alter epigenetics require metabolites as substrates or cofactors. As a result, their activities can be influenced by the metabolic state of the cell. The purpose of this review is to give an overview of cancer epigenetics and metabolism and provide examples of where they converge.

  14. Epigenetics and Vasculitis: a Comprehensive Review.

    Science.gov (United States)

    Renauer, Paul; Coit, Patrick; Sawalha, Amr H

    2016-06-01

    Vasculitides represent a group of relatively rare systemic inflammatory diseases of the blood vessels. Despite recent progress in understanding the genetic basis and the underlying pathogenic mechanisms in vasculitis, the etiology and pathogenesis of vasculitis remain incompletely understood. Epigenetic dysregulation plays an important role in immune-mediated diseases, and the contribution of epigenetic aberrancies in vasculitis is increasingly being recognized. Histone modifications in the PR3 and MPO gene loci might be mechanistically involved in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Similarly, other studies revealed important epigenetic contribution to other vasculitides, including Kawasaki disease and IgA vasculitis. More recently, genome-wide epigenomic studies have been performed in several vasculitides. A recent genome-wide DNA methylation study uncovered an important role for epigenetic remodeling of cytoskeleton-related genes in the pathogenesis of Behçet's disease and suggested that reversal of some of these DNA methylation changes associates with disease remission. Genome-wide DNA methylation profiling characterized the inflammatory response in temporal artery tissue from patients with giant cell arteritis and showed increased activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling, prompting the suggestion that a specific calcineurin/NFAT inhibitor that is well tolerated and with the added beneficial anti-platelet activity, such as dipyridamole, might be of therapeutic potential in giant cell arteritis. While epigenetic studies in systemic vasculitis are still in their infancy, currently available data clearly indicate that investigating the epigenetic mechanisms underlying these diseases will help to better understand the pathogenesis of vasculitis and provide novel targets for the development of disease biomarkers and new therapies.

  15. Epigenetic cell response to an influence of ionizing radiation

    International Nuclear Information System (INIS)

    Mikheev, A.N.; Gushcha, N.I.; Malinovskij, Yu.Yu.

    1999-01-01

    Importance of radiation modification of epigenetic activity in the general mechanism of radiobiological reactions is proved. Inheritable epigenetic changes induced by irradiation are one of the basic reasons of formation of the remote radiation pathology. It is noted that epigenetic inheritable changes of cells have the determined character distinguishing them mutation changes, being individual and not directed. It is underlined the ability of ionizing radiation to modify level of spontaneous genetic instability inherited in a number of cell generations on epigenetic mechanism [ru

  16. Nutrients and the Pancreas: An Epigenetic Perspective

    Directory of Open Access Journals (Sweden)

    Andee Weisbeck

    2017-03-01

    Full Text Available Pancreatic cancer is the fourth most common cause of cancer-related deaths with a dismal average five-year survival rate of six percent. Substitutional progress has been made in understanding how pancreatic cancer develops and progresses. Evidence is mounting which demonstrates that diet and nutrition are key factors in carcinogenesis. In particular, diets low in folate and high in fruits, vegetables, red/processed meat, and saturated fat have been identified as pancreatic cancer risk factors with a proposed mechanism involving epigenetic modifications or gene regulation. We review the current literature assessing the correlation between diet, epigenetics, and pancreatic cancer.

  17. Epigenetic control of effectors in plant pathogens

    Directory of Open Access Journals (Sweden)

    Mark eGijzen

    2014-11-01

    Full Text Available Plant pathogens display impressive versatility in adapting to host immune systems. Pathogen effector proteins facilitate disease but can become avirulence (Avr factors when the host acquires discrete recognition capabilities that trigger immunity. The mechanisms that lead to changes to pathogen Avr factors that enable escape from host immunity are diverse, and include epigenetic switches that allow for reuse or recycling of effectors. This perspective outlines possibilities of how epigenetic control of Avr effector gene expression may have arisen and persisted in plant pathogens, and how it presents special problems for diagnosis and detection of specific pathogen strains or pathotypes.

  18. Epigenetic Regulatory Mechanisms Induced by Resveratrol

    Directory of Open Access Journals (Sweden)

    Guilherme Felipe Santos Fernandes

    2017-11-01

    Full Text Available Resveratrol (RVT is one of the main natural compounds studied worldwide due to its potential therapeutic use in the treatment of many diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases and metabolic disorders. Nevertheless, the mechanism of action of RVT in all of these conditions is not completely understood, as it can modify not only biochemical pathways but also epigenetic mechanisms. In this paper, we analyze the biological activities exhibited by RVT with a focus on the epigenetic mechanisms, especially those related to DNA methyltransferase (DNMT, histone deacetylase (HDAC and lysine-specific demethylase-1 (LSD1.

  19. Epigenetic Aspects of Posttraumatic Stress Disorder

    Directory of Open Access Journals (Sweden)

    Ulrike Schmidt

    2011-01-01

    Full Text Available Development of psychiatric diseases such as posttraumatic stress disorder (PTSD invokes, as with most complex diseases, both genetic and environmental factors. The era of genome-wide high throughput technologies has sparked the initiation of genotype screenings in large cohorts of diseased and control individuals, but had limited success in identification of disease causing genetic variants. It has become evident that these efforts at the genomic level need to be complemented with endeavours in elucidating the proteome, transcriptome and epigenetic profiles. Epigenetics is attractive in particular because there is accumulating evidence that the lasting impact of adverse life events is reflected in certain covalent modifications of the chromatin.

  20. Allosteric regulation of epigenetic modifying enzymes.

    Science.gov (United States)

    Zucconi, Beth E; Cole, Philip A

    2017-08-01

    Epigenetic enzymes including histone modifying enzymes are key regulators of gene expression in normal and disease processes. Many drug development strategies to target histone modifying enzymes have focused on ligands that bind to enzyme active sites, but allosteric pockets offer potentially attractive opportunities for therapeutic development. Recent biochemical studies have revealed roles for small molecule and peptide ligands binding outside of the active sites in modulating the catalytic activities of histone modifying enzymes. Here we highlight several examples of allosteric regulation of epigenetic enzymes and discuss the biological significance of these findings. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. An introduction to the science of epigenetics

    Directory of Open Access Journals (Sweden)

    JB Thapa

    2013-03-01

    Full Text Available Epigenetics has emerged as an important new discipline. This review provides deeper insights into understanding basic defects in methylation, histone modification, and RNA induced silencing of tumours. These mechanisms have important diagnostic and therapeutic implications for many tumours and diseases. New anti-epigenetic based drug therapies have been developed and drug trials are underway. The future will see further developments in this field. Journal of Pathology of Nepal (2013 Vol. 3, No.1, Issue 5, 408-410 DOI: http://dx.doi.org/10.3126/jpn.v3i5.7870

  2. Epigenetic dominance of prion conformers.

    Directory of Open Access Journals (Sweden)

    Eri Saijo

    2013-10-01

    the otherwise unfavorable U conformer. This epigenetic mechanism thus expands the range of selectable conformations that can be adopted by PrP, and therefore the variety of options for strain propagation.

  3. Modeling evolutionary dynamics of epigenetic mutations in hierarchically organized tumors.

    Directory of Open Access Journals (Sweden)

    Andrea Sottoriva

    2011-05-01

    Full Text Available The cancer stem cell (CSC concept is a highly debated topic in cancer research. While experimental evidence in favor of the cancer stem cell theory is apparently abundant, the results are often criticized as being difficult to interpret. An important reason for this is that most experimental data that support this model rely on transplantation studies. In this study we use a novel cellular Potts model to elucidate the dynamics of established malignancies that are driven by a small subset of CSCs. Our results demonstrate that epigenetic mutations that occur during mitosis display highly altered dynamics in CSC-driven malignancies compared to a classical, non-hierarchical model of growth. In particular, the heterogeneity observed in CSC-driven tumors is considerably higher. We speculate that this feature could be used in combination with epigenetic (methylation sequencing studies of human malignancies to prove or refute the CSC hypothesis in established tumors without the need for transplantation. Moreover our tumor growth simulations indicate that CSC-driven tumors display evolutionary features that can be considered beneficial during tumor progression. Besides an increased heterogeneity they also exhibit properties that allow the escape of clones from local fitness peaks. This leads to more aggressive phenotypes in the long run and makes the neoplasm more adaptable to stringent selective forces such as cancer treatment. Indeed when therapy is applied the clone landscape of the regrown tumor is more aggressive with respect to the primary tumor, whereas the classical model demonstrated similar patterns before and after therapy. Understanding these often counter-intuitive fundamental properties of (non-hierarchically organized malignancies is a crucial step in validating the CSC concept as well as providing insight into the therapeutical consequences of this model.

  4. Future clinical trials in DIPG: bringing epigenetics to the clinic

    Directory of Open Access Journals (Sweden)

    Andres E. Morales La Madrid

    2015-07-01

    Full Text Available In spite of major recent advances in DIPG molecular characterization, this body of knowledge has not yet translated into better treatments.To date,more than 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemotherapy as well as newer biologic agents,have failed to improve the dismal outcome when compared to palliative radiation alone.The biology of DIPG remained unknown until recently when the neurosurgical expertise along with the recognition by the scientific and clinical community of the importance of tissue sampling at diagnosis;ideally in the context of a clinical trial and by trained neurosurgical teams to maximize patient safety.These pre-treatment tumor samples,and others coming from tissue obtained post-mortem,have yielded new insights into DIPG molecular biology.We now know that DIPG comprises a heterogeneous disease with variable molecular phenotypes, different from adult high grade glioma,other non-pontine pediatric high grade gliomas and even between pontine gliomas.The discovery of histone H3.3 or H3.1 mutations has been an important step forward in understanding tumor formation,maintenance and progression.Pharmacologic reversal of DIPG histone demethylation therefore offers an important potential intervention strategy for the treatment of DIPG.To date,clinical trials of newly diagnosed or progressive DIPG with epigenetic modifiers have been unsuccessful.Whether this failure represents limited activity of the agents used,their CNS penetration,redundant pathways within the tumor,or the possibility that histone mutations are necessary only to initiate DIPGs but not maintain their growth,suggest that a great deal still needs to be elucidated in both the underlying biology of these pathways,and the drugs designed to target them.In this review, we discuss the role of both epigenetic and genetic mutations within DIPG and the development of treatment strategies directed against the unique abnormalities

  5. Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes.

    Science.gov (United States)

    Xu, Ning; Chua, Angela K; Jiang, Hong; Liu, Ning-Ai; Goodarzi, Mark O

    2014-08-01

    Androgen excess is a central feature of polycystic ovary syndrome (PCOS), which affects 6% to 10% of young women. Mammals exposed to elevated androgens in utero develop PCOS-like phenotypes in adulthood, suggesting fetal origins of PCOS. We hypothesize that excess androgen exposure during early embryonic development may disturb the epigenome and disrupt metabolism in exposed and unexposed subsequent generations. Zebrafish were used to study the underlying mechanism of fetal origins. Embryos were exposed to androgens (testosterone and dihydrotestosterone) early at 26 to 56 hours post fertilization or late at 21 to 28 days post fertilization. Exposed zebrafish (F0) were grown to adults and crossed to generate unexposed offspring (F1). For both generations, global DNA methylation levels were examined in ovaries using a luminometric methylation assay, and fasting and postprandial blood glucose levels were measured. We found that early but not late androgen exposure induced changes in global methylation and glucose homeostasis in both generations. In general, F0 adult zebrafish exhibited altered global methylation levels in the ovary; F1 zebrafish had global hypomethylation. Fasting blood glucose levels were decreased in F0 but increased in F1; postprandial glucose levels were elevated in both F0 and F1. This androgenized zebrafish study suggests that transient excess androgen exposure during early development can result in transgenerational alterations in the ovarian epigenome and glucose homeostasis. Current data cannot establish a causal relationship between epigenetic changes and altered glucose homeostasis. Whether transgenerational epigenetic alteration induced by prenatal androgen exposure plays a role in the development of PCOS in humans deserves study.

  6. Advances on research epigenetic change of hybrid and polyploidy ...

    African Journals Online (AJOL)

    A large proportion of these variations are epigenetic in nature. Epigenetic can be defined as a change of the study in the regulation of gene activity and expression that are not driven by gene sequence information. However, the ramifications of epigenetic in plant biology are immense, yet unappreciated. In contrast to the ...

  7. Epigenetic alteration of sedimentary rocks at hydrogenic uranium deposit

    International Nuclear Information System (INIS)

    Ding Wanlie; Shen Kefeng

    2001-01-01

    The author introduces the concept, the recognition criteria, the genesis and classification of the epigenetic alteration of sedimentary rocks in brief, and expounds the mineral-geochemical indications and characteristics of oxidation and reduction alterations in different geochemical zones in detail, and proposes the two models of ore-controlling zonation of epigenetic alteration. The authors finally introduce research methods of epigenetic alteration

  8. Epigenetics Europe conference. Munich, Germany, 8-9 September 2011.

    Science.gov (United States)

    Jeltsch, Albert

    2011-12-01

    At the Epigenetics Europe conference in Munich, Germany, held on 8-9 September 2011, 19 speakers from different European countries were presenting novel data and concepts on molecular epigenetics. The talks were mainly focused on questions of the generation, maintenance, flexibility and erasure of DNA methylation patterns in context of other epigenetic signals like histone tail modifications and ncRNAs.

  9. Introduction to the Special Section on Epigenetics

    Science.gov (United States)

    Lester, Barry M.; Conradt, Elisabeth; Marsit, Carmen

    2016-01-01

    Epigenetics provides the opportunity to revolutionize our understanding of the role of genetics and the environment in explaining human behavior, although the use of epigenetics to study human behavior is just beginning. In this introduction, the authors present the basics of epigenetics in a way that is designed to make this exciting field…

  10. Gene expression and stress response mediated by the epigenetic regulation of a transposable element small RNA.

    Directory of Open Access Journals (Sweden)

    Andrea D McCue

    2012-02-01

    Full Text Available The epigenetic activity of transposable elements (TEs can influence the regulation of genes; though, this regulation is confined to the genes, promoters, and enhancers that neighbor the TE. This local cis regulation of genes therefore limits the influence of the TE's epigenetic regulation on the genome. TE activity is suppressed by small RNAs, which also inhibit viruses and regulate the expression of genes. The production of TE heterochromatin-associated endogenous small interfering RNAs (siRNAs in the reference plant Arabidopsis thaliana is mechanistically distinct from gene-regulating small RNAs, such as microRNAs or trans-acting siRNAs (tasiRNAs. Previous research identified a TE small RNA that potentially regulates the UBP1b mRNA, which encodes an RNA-binding protein involved in stress granule formation. We demonstrate that this siRNA, siRNA854, is under the same trans-generational epigenetic control as the Athila family LTR retrotransposons from which it is produced. The epigenetic activation of Athila elements results in a shift in small RNA processing pathways, and new 21-22 nucleotide versions of Athila siRNAs are produced by protein components normally not responsible for processing TE siRNAs. This processing results in siRNA854's incorporation into ARGONAUTE1 protein complexes in a similar fashion to gene-regulating tasiRNAs. We have used reporter transgenes to demonstrate that the UPB1b 3' untranslated region directly responds to the epigenetic status of Athila TEs and the accumulation of siRNA854. The regulation of the UPB1b 3' untranslated region occurs both on the post-transcriptional and translational levels when Athila TEs are epigenetically activated, and this regulation results in the phenocopy of the ubp1b mutant stress-sensitive phenotype. This demonstrates that a TE's epigenetic activity can modulate the host organism's stress response. In addition, the ability of this TE siRNA to regulate a gene's expression in trans blurs

  11. Epigenetic Modulation of the Biophysical Properties of Drug-Resistant Cell Lipids to Restore Drug Transport and Endocytic Functions

    OpenAIRE

    Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

    2012-01-01

    In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g....

  12. The molecular and mathematical basis of Waddington's epigenetic landscape: a framework for post-Darwinian biology?

    Science.gov (United States)

    Huang, Sui

    2012-02-01

    The Neo-Darwinian concept of natural selection is plausible when one assumes a straightforward causation of phenotype by genotype. However, such simple 1:1 mapping must now give place to the modern concepts of gene regulatory networks and gene expression noise. Both can, in the absence of genetic mutations, jointly generate a diversity of inheritable randomly occupied phenotypic states that could also serve as a substrate for natural selection. This form of epigenetic dynamics challenges Neo-Darwinism. It needs to incorporate the non-linear, stochastic dynamics of gene networks. A first step is to consider the mathematical correspondence between gene regulatory networks and Waddington's metaphoric 'epigenetic landscape', which actually represents the quasi-potential function of global network dynamics. It explains the coexistence of multiple stable phenotypes within one genotype. The landscape's topography with its attractors is shaped by evolution through mutational re-wiring of regulatory interactions - offering a link between genetic mutation and sudden, broad evolutionary changes. Copyright © 2012 WILEY Periodicals, Inc.

  13. Dystrophic Cardiomyopathy: Complex Pathobiological Processes to Generate Clinical Phenotype

    Directory of Open Access Journals (Sweden)

    Takeshi Tsuda

    2017-09-01

    Full Text Available Duchenne muscular dystrophy (DMD, Becker muscular dystrophy (BMD, and X-linked dilated cardiomyopathy (XL-DCM consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic mechanisms in forming dystrophic cardiomyopathy. In this review article, we review the complex molecular interactions involving the pathogenesis of dystrophic cardiomyopathy, including primary gene mutations and loss of structural integrity, secondary cellular responses, and certain epigenetic and other factors that modulate gene expressions. Involvement of epigenetic gene regulation appears to lead to specific cardiac phenotypes in dystrophic hearts.

  14. CROSSOVERS BETWEEN EPIGENESIS AND EPIGENETICS. A MULTICENTER APPROACH TO THE HISTORY OF EPIGENETICS (1901-1975).

    Science.gov (United States)

    Costa, Rossella; Frezza, Giulia

    2014-01-01

    The origin of epigenetics has been traditionally traced back to Conrad Hal Waddington's foundational work in 1940s. The aim of the present paper is to reveal a hidden history of epigenetics, by means of a multicenter approach. Our analysis shows that genetics and embryology in early XX century--far from being non-communicating vessels--shared similar questions, as epitomized by Thomas Hunt Morgan's works. Such questions were rooted in the theory of epigenesis and set the scene for the development of epigenetics. Since the 1950s, the contribution of key scientists (Mary Lyon and Eduardo Scarano), as well as the discussions at the international conference of Gif-sur-Yvette (1957) paved the way for three fundamental shifts of focus: 1. From the whole embryo to the gene; 2. From the gene to the complex extranuclear processes of development; 3. From cytoplasmic inheritance to the epigenetics mechanisms.

  15. Conference Scene: epigenetics eh! The first formal meeting of the Canadian epigenetics community.

    Science.gov (United States)

    Underhill, Alan; Hendzel, Michael J

    2011-08-01

    In recognition of Canada's longstanding interest in epigenetics - and a particular linguistic interjection - the inaugural 'Epigenetics, Eh!' conference was held between 4-7 May 2011 in London, Ontario. The meeting struck an excellent balance between Canadian and international leaders in epigenetic research while also providing a venue to showcase up-and-coming talent. Almost without exception, presentations touched on the wide-ranging and severe consequences of epigenetic dysfunction, as well as current and emerging therapeutic opportunities. While gaining a deeper understanding of how DNA and histone modifications, together with multiple classes of ncRNAs, act to functionalize our genome, participants were also provided with a glimpse of the astounding complexity of chromatin structure, challenging existing dogma.

  16. The placental gateway of maternal transgenerational epigenetic ...

    Indian Academy of Sciences (India)

    While much of our understanding of genetic inheritance is based on the genome of the organism, it is becoming clear that there is an ample amount of epigenetic inheritance, which though reversible, escapes erasing process during gametogenesis and goes on to the next generation. Several examples of transgenerational ...

  17. [Epigenetic alterations in acute lymphoblastic leukemia].

    Science.gov (United States)

    Navarrete-Meneses, María Del Pilar; Pérez-Vera, Patricia

    Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. It is well-known that genetic alterations constitute the basis for the etiology of ALL. However, genetic abnormalities are not enough for the complete development of the disease, and additional alterations such as epigenetic modifications are required. Such alterations, like DNA methylation, histone modifications, and noncoding RNA regulation have been identified in ALL. DNA hypermethylation in promoter regions is one of the most frequent epigenetic modifications observed in ALL. This modification frequently leads to gene silencing in tumor suppressor genes, and in consequence, contributes to leukemogenesis. Alterations in histone remodeling proteins have also been detected in ALL, such as the overexpression of histone deacetylases enzymes, and alteration of acetyltransferases and methyltransferases. ALL also shows alteration in the expression of miRNAs, and in consequence, the modification in the expression of their target genes. All of these epigenetic modifications are key events in the malignant transformation since they lead to the deregulation of oncogenes as BLK, WNT5B and WISP1, and tumor suppressors such as FHIT, CDKN2A, CDKN2B, and TP53, which alter fundamental cellular processes and potentially lead to the development of ALL. Both genetic and epigenetic alterations contribute to the development and evolution of ALL. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

  18. Epigenetic regulation of caloric restriction in aging

    Directory of Open Access Journals (Sweden)

    Daniel Michael

    2011-08-01

    Full Text Available Abstract The molecular mechanisms of aging are the subject of much research and have facilitated potential interventions to delay aging and aging-related degenerative diseases in humans. The aging process is frequently affected by environmental factors, and caloric restriction is by far the most effective and established environmental manipulation for extending lifespan in various animal models. However, the precise mechanisms by which caloric restriction affects lifespan are still not clear. Epigenetic mechanisms have recently been recognized as major contributors to nutrition-related longevity and aging control. Two primary epigenetic codes, DNA methylation and histone modification, are believed to dynamically influence chromatin structure, resulting in expression changes of relevant genes. In this review, we assess the current advances in epigenetic regulation in response to caloric restriction and how this affects cellular senescence, aging and potential extension of a healthy lifespan in humans. Enhanced understanding of the important role of epigenetics in the control of the aging process through caloric restriction may lead to clinical advances in the prevention and therapy of human aging-associated diseases.

  19. Epigenetic effects of human breast milk.

    Science.gov (United States)

    Verduci, Elvira; Banderali, Giuseppe; Barberi, Salvatore; Radaelli, Giovanni; Lops, Alessandra; Betti, Federica; Riva, Enrica; Giovannini, Marcello

    2014-04-24

    A current aim of nutrigenetics is to personalize nutritional practices according to genetic variations that influence the way of digestion and metabolism of nutrients introduced with the diet. Nutritional epigenetics concerns knowledge about the effects of nutrients on gene expression. Nutrition in early life or in critical periods of development, may have a role in modulating gene expression, and, therefore, have later effects on health. Human breast milk is well-known for its ability in preventing several acute and chronic diseases. Indeed, breastfed children may have lower risk of neonatal necrotizing enterocolitis, infectious diseases, and also of non-communicable diseases, such as obesity and related-disorders. Beneficial effects of human breast milk on health may be associated in part with its peculiar components, possible also via epigenetic processes. This paper discusses about presumed epigenetic effects of human breast milk and components. While evidence suggests that a direct relationship may exist of some components of human breast milk with epigenetic changes, the mechanisms involved are still unclear. Studies have to be conducted to clarify the actual role of human breast milk on genetic expression, in particular when linked to the risk of non-communicable diseases, to potentially benefit the infant's health and his later life.

  20. Concepts of epigenetics in prostate cancer development.

    Science.gov (United States)

    Cooper, C S; Foster, C S

    2009-01-27

    Substantial evidence now supports the view that epigenetic changes have a role in the development of human prostate cancer. Analyses of the patterns of epigenetic alteration are providing important insights into the origin of this disease and have identified specific alterations that may serve as useful diagnostic and prognostic biomarkers. Examination of cancer methylation patterns supports a stem cell origin of prostate cancer. It is well established that methylation of GSTpi is a marker of prostate cancer, and global patterns of histone marking appear to be linked to cancer prognosis with levels of acetylated histones H3K9, H3K18, and H4K12, and of dimethylated H4R3 and H3K4, dividing low-grade prostate cancer (Gleason 6 or less) into two prognostically separate groups. Elevated levels of several components of the polycomb group protein complex, EZH2, BMI1, and RING1, can also act as biomarkers of poor clinical outcome. Many components of the epigenetic machinery, including histone deacetylase (whose expression level is linked to the TMPRSS2:ERG translocation) and the histone methylase EZH2, are potential therapeutic targets. The recent discovery of the role of small RNAs in governing the epigenetic status of individual genes offers exciting new possibilities in therapeutics and chemoprevention.

  1. Metabolic-epigenetic crosstalk in macrophage activation

    NARCIS (Netherlands)

    Baardman, Jeroen; Licht, Iris; de Winther, Menno P. J.; van den Bossche, Jan

    2015-01-01

    Epigenetic enzymes are emerging as crucial controllers of macrophages, innate immune cells that determine the outcome of many inflammatory diseases. Recent studies demonstrate that the activity of particular chromatin-modifying enzymes is regulated by the availability of specific metabolites like

  2. Epigenetics and the Social Work Imperative

    Science.gov (United States)

    Combs-Orme, Terri

    2013-01-01

    "Epigenesis" is the biochemical process through which some genes are expressed and others remain silent, and it reinforces and explains the powerful impact that the environment has on human development. Epigenetic effects occur not only through diet, chemical exposure, and high levels of environmental stress, but also through chronic poverty and…

  3. Mitochondrial epigenetics : an overlooked layer of regulation?

    NARCIS (Netherlands)

    van der Wijst, Monique G. P.; Rots, Marianne G.

    Despite decades of research, mitochondrial epigenetics remains a controversial notion. Recent findings, however, indicate that dysfunctional mitochondrial DNA (mtDNA) methylation could underlie aging and disease. Unraveling such a level of regulation will be essential in the understanding of and in

  4. Epigenetics as a First Exit Problem

    Science.gov (United States)

    Aurell, E.; Sneppen, K.

    2002-01-01

    We develop a framework to discuss the stability of epigenetic states as first exit problems in dynamical systems with noise. We consider in particular the stability of the lysogenic state of the λ prophage. The formalism defines a quantitative measure of robustness of inherited states.

  5. Epigenetics ELSI: Darker Than You Think?

    Science.gov (United States)

    Joly, Yann; So, Derek; Saulnier, Katie; Dyke, Stephanie O M

    2016-10-01

    Emerging ethical, legal, and social implications (ELSI) scholarship in epigenetics has focused largely on hypothetical issues involving institutional racism, discrimination, and eugenics. To avoid an unwarranted backlash against this promising research field, we encourage a more balanced ELSI discussion conveying the full spectrum of issues faced by stakeholders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Epigenetics of inflammation, maternal infection and nutrition

    Science.gov (United States)

    Studies have demonstrated that epigenetic changes such as DNA methylation, histone modification, and chromatin remodeling are linked to an increased inflammatory response as well as increased risk for chronic disease development. A few studies have begun to investigate whether dietary nutrients play...

  7. Epigenetics: Making your mark on DNA

    Science.gov (United States)

    Harada, Bryan T.; He, Chuan

    2017-11-01

    Understanding the biological roles of modifications to DNA, RNA and proteins is critical to revealing how cells regulate gene expression in development and disease. Two papers now present a combination of new tools and discoveries that could enable biologists and chemical biologists to better study epigenetic regulation in mammals.

  8. Dietary effects on adipocyte metabolism and epigenetics

    Science.gov (United States)

    Obesity risk appears to be perpetuated across generations by way of programmed DNA alterations that occur in utero and that affect gene expression throughout the life span. Studies have demonstrated associations of maternal obesity and epigenetic changes, such as DNA methylation, histone modifica...

  9. Epigenetic Effects of Human Breast Milk

    Directory of Open Access Journals (Sweden)

    Elvira Verduci

    2014-04-01

    Full Text Available A current aim of nutrigenetics is to personalize nutritional practices according to genetic variations that influence the way of digestion and metabolism of nutrients introduced with the diet. Nutritional epigenetics concerns knowledge about the effects of nutrients on gene expression. Nutrition in early life or in critical periods of development, may have a role in modulating gene expression, and, therefore, have later effects on health. Human breast milk is well-known for its ability in preventing several acute and chronic diseases. Indeed, breastfed children may have lower risk of neonatal necrotizing enterocolitis, infectious diseases, and also of non-communicable diseases, such as obesity and related-disorders. Beneficial effects of human breast milk on health may be associated in part with its peculiar components, possible also via epigenetic processes. This paper discusses about presumed epigenetic effects of human breast milk and components. While evidence suggests that a direct relationship may exist of some components of human breast milk with epigenetic changes, the mechanisms involved are still unclear. Studies have to be conducted to clarify the actual role of human breast milk on genetic expression, in particular when linked to the risk of non-communicable diseases, to potentially benefit the infant’s health and his later life.

  10. Epigenetic Risk Factors in PTSD and Depression

    Directory of Open Access Journals (Sweden)

    Florian Joachim Raabe

    2013-08-01

    Full Text Available Epidemiological and clinical studies have shown that children exposed to adverse experiences are at increased risk for the development of depression, anxiety disorders and PTSD. A history of child abuse and maltreatment increases the likelihood of being subsequently exposed to traumatic events or of developing PTSD as an adult. The brain is highly plastic during early life and encodes acquired information into lasting memories that normally subserve adaptation. Translational studies in rodents showed that enduring sensitization of neuronal and neuroendocrine circuits in response to early life adversity are likely risk factors of life time vulnerability to stress. Hereby, the hypothalamic-pituitary-adrenal (HPA axis integrates cognitive, behavioural and emotional responses to early-life stress and can be epigenetically programmed during sensitive windows of development. Epigenetic mechanisms, comprising reciprocal regulation of chromatin structure and DNA methylation, are important to establish and maintain sustained, yet potentially reversible, changes in gene transcription. The relevance of these findings for the development of PTSD requires further studies in humans where experience-dependent epigenetic programming can additionally depend on genetic variation in the underlying substrates which may protect from or advance disease development. Overall, identification of early-life stress associated epigenetic risk markers informing on previous stress history can help to advance early diagnosis, personalized prevention and timely therapeutic interventions, thus reducing long-term social and health costs.

  11. Epigenetic architecture and miRNA: reciprocal regulators

    DEFF Research Database (Denmark)

    Wiklund, Erik D; Kjems, Jørgen; Clark, Susan J

    2010-01-01

    Deregulation of epigenetic and microRNA (miRNA) pathways are emerging as key events in carcinogenesis. miRNA genes can be epigenetically regulated and miRNAs can themselves repress key enzymes that drive epigenetic remodeling. Epigenetic and miRNA functions are thus tightly interconnected......RNAs) are considered especially promising in clinical applications, and their biogenesis and function is a subject of active research. In this review, the current status of epigenetic miRNA regulation is summarized and future therapeutic prospects in the field are discussed with a focus on cancer....

  12. Epigenetic and conventional regulation is distributed among activators of FLO11 allowing tuning of population-level heterogeneity in its expression.

    Directory of Open Access Journals (Sweden)

    Leah M Octavio

    2009-10-01

    Full Text Available Epigenetic switches encode their state information either locally, often via covalent modification of DNA or histones, or globally, usually in the level of a trans-regulatory factor. Here we examine how the regulation of cis-encoded epigenetic switches controls the extent of heterogeneity in gene expression, which is ultimately tied to phenotypic diversity in a population. We show that two copies of the FLO11 locus in Saccharomyces cerevisiae switch between a silenced and competent promoter state in a random and independent fashion, implying that the molecular event leading to the transition occurs locally at the promoter, in cis. We further quantify the effect of trans regulators both on the slow epigenetic transitions between a silenced and competent promoter state and on the fast promoter transitions associated with conventional regulation of FLO11. We find different classes of regulators affect epigenetic, conventional, or both forms of regulation. Distributing kinetic control of epigenetic silencing and conventional gene activation offers cells flexibility in shaping the distribution of gene expression and phenotype within a population.

  13. The physics of cancer: The role of epigenetics and chromosome conformation in cancer progression

    Energy Technology Data Exchange (ETDEWEB)

    Naimark, Oleg B.; Nikitiuk, Aleksandr S. [Institute of Continuous Media Mechanics UrB RAS, Perm, 614013 (Russian Federation); Baudement, Marie-Odile; Forné, Thierry [Institut de Génétique Moléculaire de Montpellier UMR 5535, CNRS, Université de Montpellier, 1919 route de Mende, Montpellier cedex 5, 34293 France (France); Lesne, Annick, E-mail: annick.lesne@igmm.cnrs.fr [Institut de Génétique Moléculaire de Montpellier UMR 5535, CNRS, Université de Montpellier, 1919 route de Mende, Montpellier cedex 5, 34293 France (France); Laboratoire de Physique Théorique de la Matière Condensée UMR 7600, CNRS, UPMC, Sorbonne Universités, 4 place Jussieu, Paris cedex 5, 75252 France (France)

    2016-08-02

    Cancer progression is generally described in terms of accumulated genetic alterations and ensuing changes in cell properties. However, intermediary modifications are involved in the establishment of cancer cell phenotypes, at different levels of nuclear organization: DNA damages and their structural consequences, epigenetic modifications and their impact on chromatin architecture, changes in chromosome 3D organization. We review some of these alterations with a focus on their physical aspects. The challenge is to understand the multiscale interplay between generic physical mechanisms and specific biological factors in cancer cells. We argue that such an interdisciplinary perspective offers a novel viewpoint on cancer progression, early diagnosis and possibly therapeutic targets.

  14. Neurofibromatosis-Noonan Syndrome: A Possible Paradigm of the Combination of Genetic and Epigenetic Factors.

    Science.gov (United States)

    Yapijakis, Christos; Pachis, Nikos; Voumvourakis, Costas

    2017-01-01

    Neurofibromatosis-Noonan syndrome (NFNS) is a clinical entity possessing traits of autosomal dominant disorders neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). Germline mutations that disrupt the RAS/MAPK pathway are involved in the pathogenesis of both NS and NF1. In light of a studied Greek family, a new theory for etiological pathogenesis of NFNS is suggested. The NFNS phenotype may be the final result of a combination of a genetic factor (a mutation in the NF1 gene) and an environmental factor with the epigenetic effects of muscle hypotonia (such as hydantoin in the reported Greek family), causing hypoplasia of the face and micrognathia.

  15. Morphological analysis and DNA methylation in Conyza bonariensis L. cronquist (Asteraceae phenotypes

    Directory of Open Access Journals (Sweden)

    Juliana Maria de Paula

    2017-08-01

    Full Text Available ABSTRACT The species Conyza bonariensis (L. cause losses in agriculture due to their invasive capacity and resistance to herbicides like glyphosate. The species of this genus exhibit phenotypic plasticity, which complicates their identification and characterization. Thus, experiments were performed with 2 extreme C. bonariensis phenotypes (called broad leaf and narrow leaf in greenhouse conditions and in the laboratory, in order to verify if the morphological differences among these phenotypes are a genetic character or result from environmental effects. In addition to the comparative morphological analysis, assessment of DNA methylation profile was performed to detect the occurrence, or not, of differences in the epigenetic level. The morphological characteristics evaluated were length, width, shape, margin and leaves indument; plant height and stem indument; the number of capitula, flowers and seeds. The Methylation Sensitive Amplified Polymorphism technique was used to investigate the methylation levels. The morphological differences of phenotypes supposed to be C. bonariensis are probably genetic in origin and not the result of environmental effects, since, after 6 crop cycles in a greenhouse under the same environmental conditions, these phenotypes remained with the same morphological characteristics and seed production in relation to the original phenotypes found in the collection site. The different phenotypes did not show differences corresponding to DNA methylation patterns that could indicate an epigenetic effect as the cause of the differences between the 2 phenotypes. The results of morphological analysis and methylation probably indicate that maybe they are individuals of populations from different taxa not registered yet in the literature.

  16. Epigenetics: general characteristics and implications for oral health

    Directory of Open Access Journals (Sweden)

    Ji-Yun Seo

    2015-02-01

    Full Text Available Genetic information such as DNA sequences has been limited to fully explain mechanisms of gene regulation and disease process. Epigenetic mechanisms, which include DNA methylation, histone modification and non-coding RNAs, can regulate gene expression and affect progression of disease. Although studies focused on epigenetics are being actively investigated in the field of medicine and biology, epigenetics in dental research is at the early stages. However, studies on epigenetics in dentistry deserve attention because epigenetic mechanisms play important roles in gene expression during tooth development and may affect oral diseases. In addition, understanding of epigenetic alteration is important for developing new therapeutic methods. This review article aims to outline the general features of epigenetic mechanisms and describe its future implications in the field of dentistry.

  17. Comparative in silico profiling of epigenetic modifiers in human tissues.

    Science.gov (United States)

    Son, Mi-Young; Jung, Cho-Rok; Kim, Dae-Soo; Cho, Hyun-Soo

    2018-04-06

    The technology of tissue differentiation from human pluripotent stem cells has attracted attention as a useful resource for regenerative medicine, disease modeling and drug development. Recent studies have suggested various key factors and specific culture methods to improve the successful tissue differentiation and efficient generation of human induced pluripotent stem cells. Among these methods, epigenetic regulation and epigenetic signatures are regarded as an important hurdle to overcome during reprogramming and differentiation. Thus, in this study, we developed an in silico epigenetic panel and performed a comparative analysis of epigenetic modifiers in the RNA-seq results of 32 human tissues. We demonstrated that an in silico epigenetic panel can identify epigenetic modifiers in order to overcome epigenetic barriers to tissue-specific differentiation.

  18. Epigenetic Variance, Performing Cooperative Structure with Genetics, Is Associated with Leaf Shape Traits in Widely Distributed Populations of Ornamental Tree Prunus mume

    Directory of Open Access Journals (Sweden)

    Kaifeng Ma

    2018-01-01

    Full Text Available Increasing evidence shows that epigenetics plays an important role in phenotypic variance. However, little is known about epigenetic variation in the important ornamental tree Prunus mume. We used amplified fragment length polymorphism (AFLP and methylation-sensitive amplified polymorphism (MSAP techniques, and association analysis and sequencing to investigate epigenetic variation and its relationships with genetic variance, environment factors, and traits. By performing leaf sampling, the relative total methylation level (29.80% was detected in 96 accessions of P. mume. And the relative hemi-methylation level (15.77% was higher than the relative full methylation level (14.03%. The epigenetic diversity (I∗ = 0.575, h∗ = 0.393 was higher than the genetic diversity (I = 0.484, h = 0.319. The cultivated population displayed greater epigenetic diversity than the wild populations in both southwest and southeast China. We found that epigenetic variance and genetic variance, and environmental factors performed cooperative structures, respectively. In particular, leaf length, width and area were positively correlated with relative full methylation level and total methylation level, indicating that the DNA methylation level played a role in trait variation. In total, 203 AFLP and 423 MSAP associated markers were detected and 68 of them were sequenced. Homologous analysis and functional prediction suggested that the candidate marker-linked genes were essential for leaf morphology development and metabolism, implying that these markers play critical roles in the establishment of leaf length, width, area, and ratio of length to width.

  19. Epigenetic Variance, Performing Cooperative Structure with Genetics, Is Associated with Leaf Shape Traits in Widely Distributed Populations of Ornamental Tree Prunus mume.

    Science.gov (United States)

    Ma, Kaifeng; Sun, Lidan; Cheng, Tangren; Pan, Huitang; Wang, Jia; Zhang, Qixiang

    2018-01-01

    Increasing evidence shows that epigenetics plays an important role in phenotypic variance. However, little is known about epigenetic variation in the important ornamental tree Prunus mume . We used amplified fragment length polymorphism (AFLP) and methylation-sensitive amplified polymorphism (MSAP) techniques, and association analysis and sequencing to investigate epigenetic variation and its relationships with genetic variance, environment factors, and traits. By performing leaf sampling, the relative total methylation level (29.80%) was detected in 96 accessions of P . mume . And the relative hemi-methylation level (15.77%) was higher than the relative full methylation level (14.03%). The epigenetic diversity ( I ∗ = 0.575, h ∗ = 0.393) was higher than the genetic diversity ( I = 0.484, h = 0.319). The cultivated population displayed greater epigenetic diversity than the wild populations in both southwest and southeast China. We found that epigenetic variance and genetic variance, and environmental factors performed cooperative structures, respectively. In particular, leaf length, width and area were positively correlated with relative full methylation level and total methylation level, indicating that the DNA methylation level played a role in trait variation. In total, 203 AFLP and 423 MSAP associated markers were detected and 68 of them were sequenced. Homologous analysis and functional prediction suggested that the candidate marker-linked genes were essential for leaf morphology development and metabolism, implying that these markers play critical roles in the establishment of leaf length, width, area, and ratio of length to width.

  20. Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions.

    Science.gov (United States)

    Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

    2012-09-04

    In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane's biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug 5-aza-2'-deoxycytidine (decitabine) significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.

  1. Rosaceae Fruit Development, Ripening and Post-harvest: An Epigenetic Perspective.

    Science.gov (United States)

    Farinati, Silvia; Rasori, Angela; Varotto, Serena; Bonghi, Claudio

    2017-01-01

    Rosaceae is a family with an extraordinary spectrum of fruit types, including fleshy peach, apple, and strawberry that provide unique contributions to a healthy diet for consumers, and represent an excellent model for studying fruit patterning and development. In recent years, many efforts have been made to unravel regulatory mechanism underlying the hormonal, transcriptomic, proteomic and metabolomic changes occurring during Rosaceae fruit development. More recently, several studies on fleshy (tomato) and dry (Arabidopsis) fruit model have contributed to a better understanding of epigenetic mechanisms underlying important heritable crop traits, such as ripening and stress response. In this context and summing up the results obtained so far, this review aims to collect the available information on epigenetic mechanisms that may provide an additional level in gene transcription regulation, thus influencing and driving the entire Rosaceae fruit developmental process. The whole body of information suggests that Rosaceae fruit could become also a model for studying the epigenetic basis of economically important phenotypes, allowing for their more efficient exploitation in plant breeding.

  2. Impact of nutrition on noncoding RNA epigenetics in breast and gynecological cancer

    Directory of Open Access Journals (Sweden)

    Rosanna H. E. Krakowsky

    2015-05-01

    Full Text Available Cancer is the second leading cause of death in females. According to the American Cancer Society, there are 327,660 new cases in breast and gynecological cancers estimated in 2014, placing emphasis on the need for cancer prevention and new cancer treatment strategies. One important approach to cancer prevention involves phytochemicals, biologically active compounds derived from plants. A variety of studies on the impact of dietary compounds found in cruciferous vegetables, green tea and spices like curry and black pepper have revealed epigenetic changes in female cancers. Thus, an important emerging topic comprises epigenetic changes due to the modulation of noncoding RNA levels. Since it has been shown that noncoding RNAs such as microRNAs and long noncoding RNAs are aberrantly expressed in cancer and furthermore are linked to distinct cancer phenotypes, understanding the effects of dietary compounds and supplements on the epigenetic modulator noncoding RNA is of great interest. This article reviews the current findings on nutrition-induced changes in breast and gynecological cancers at the noncoding RNA level.

  3. Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs.

    Science.gov (United States)

    Schuster, Andrew; Skinner, Michael K; Yan, Wei

    Exposure to the agricultural fungicide vinclozolin during gestation promotes a higher incidence of various diseases in the subsequent unexposed F3 and F4 generations. This phenomenon is termed epigenetic transgenerational inheritance and has been shown to in part involve alterations in DNA methylation, but the role of other epigenetic mechanisms remains unknown. The current study investigated the alterations in small noncoding RNA (sncRNA) in the sperm from F3 generation control and vinclozolin lineage rats. Over 200 differentially expressed sncRNAs were identified and the tRNA-derived sncRNAs, namely 5' halves of mature tRNAs (5' halves), displayed the most dramatic changes. Gene targets of the altered miRNAs and tRNA 5' halves revealed associations between the altered sncRNAs and differentially DNA methylated regions. Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed vinclozolin-induced disease phenotypes. Data suggest potential connections between sperm-borne RNAs and the vinclozolin-induced epigenetic transgenerational inheritance phenomenon.

  4. A unique epigenetic signature is associated with active DNA replication loci in human embryonic stem cells.

    Science.gov (United States)

    Li, Bing; Su, Trent; Ferrari, Roberto; Li, Jing-Yu; Kurdistani, Siavash K

    2014-02-01

    The cellular epigenetic landscape changes as pluripotent stem cells differentiate to somatic cells or when differentiated cells transform to a cancerous state. These epigenetic changes are commonly correlated with differences in gene expression. Whether active DNA replication is also associated with distinct chromatin environments in these developmentally and phenotypically diverse cell types has not been known. Here, we used BrdU-seq to map active DNA replication loci in human embryonic stem cells (hESCs), normal primary fibroblasts and a cancer cell line, and correlated these maps to the epigenome. In all cell lines, the majority of BrdU peaks were enriched in euchromatin and at DNA repetitive elements, especially at microsatellite repeats, and coincided with previously determined replication origins. The most prominent BrdU peaks were shared between all cells but a sizable fraction of the peaks were specific to each cell type and associated with cell type-specific genes. Surprisingly, the BrdU peaks that were common to all cell lines were associated with H3K18ac, H3K56ac, and H4K20me1 histone marks only in hESCs but not in normal fibroblasts or cancer cells. Depletion of the histone acetyltransferases for H3K18 and H3K56 dramatically decreased the number and intensity of BrdU peaks in hESCs. Our data reveal a unique epigenetic signature that distinguishes active replication loci in hESCs from normal somatic or malignant cells.

  5. Phenotype heterogeneity in cancer cell populations

    International Nuclear Information System (INIS)

    Almeida, Luis; Chisholm, Rebecca; Clairambault, Jean; Escargueil, Alexandre; Lorenzi, Tommaso; Lorz, Alexander; Trélat, Emmanuel

    2016-01-01

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as “bet hedging” of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  6. Phenotype heterogeneity in cancer cell populations

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, Luis [CNRS UMR 7598, LJLL, & INRIA MAMBA team, Sorbonne Universités, UPMC Univ Paris 06, Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, luis@ann.jussieu.fr (France); Chisholm, Rebecca [School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia, rebecca.chisholm@gmail.com (Australia); Clairambault, Jean [INRIA MAMBA team & LJLL, UMR 7598, Sorbonne Universités, UPMC Univ Paris 06, Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, jean.clairambault@inria.fr, Corresponding author (France); Escargueil, Alexandre [INSERM “Cancer Biology and Therapeutics”, Sorbonne Universités, UPMC Univ Paris 06, UMR-S 938, CDR St Antoine, Hôpital St Antoine, 184 Fbg. St Antoine, 75571 Paris cedex 12, France, alexandre.escargueil@upmc.fr (France); Lorenzi, Tommaso [CMLA, ENS Cachan, 61, Av. du Président Wilson, 94230 Cachan cedex & INRIA MAMBA team, & LJLL, UMR 7598, UPMC Univ Paris 06, Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, tommaso.lorenzi@gmail.com (France); Lorz, Alexander [Sorbonne Universités, UPMC Univ Paris 06, LJLL, UMR 7598 & INRIA Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, alex.lorz@ann.jussieu.fr (France); Trélat, Emmanuel [Institut Universitaire de France, Sorbonne Universités, UPMC Univ Paris 06, LJLL, UMR 7598, Boîte courrier 187, UPMC Univ Paris 06, 4 Pl. Jussieu, 75252 Paris cedex 05, France, emmanuel.trelat@upmc.fr (France)

    2016-06-08

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as “bet hedging” of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  7. Phenotype heterogeneity in cancer cell populations

    Science.gov (United States)

    Almeida, Luis; Chisholm, Rebecca; Clairambault, Jean; Escargueil, Alexandre; Lorenzi, Tommaso; Lorz, Alexander; Trélat, Emmanuel

    2016-06-01

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as "bet hedging" of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  8. Epigenetic Mechanisms and Therapeutic Perspectives for Neurodevelopmental Disorders

    Directory of Open Access Journals (Sweden)

    Kunio Miyake

    2012-04-01

    Full Text Available The number of children with mild neurodevelopmental disorders, such as autism, has been recently increasing in advanced countries. This increase is probably caused by environmental factors rather than genetic factors, because it is unlikely that genetic mutation rates suddenly increased within a short period. Epigenetics is a mechanism that regulates gene expression, depending not on the underlying DNA sequence but on the chemical modifications of DNA and histone proteins. Because mental stress can alter the epigenetic status in neuronal cells, environmental factors may alter brain function through epigenetic changes. However, one advantage of epigenetic changes is their reversibility. Therefore, diseases due to abnormal epigenetic regulation are theoretically treatable. In fact, several drugs for treating mental diseases are known to have restoring effects on aberrant epigenetic statuses, and a novel therapeutic strategy targeting gene has been developed. In this review, we discuss epigenetic mechanisms of congenital and acquired neurodevelopmental disorders, drugs with epigenetic effects, novel therapeutic strategies for epigenetic diseases, and future perspectives in epigenetic medicine.

  9. Bioinformatics Tools for Genome-Wide Epigenetic Research.

    Science.gov (United States)

    Angarica, Vladimir Espinosa; Del Sol, Antonio

    2017-01-01

    Epigenetics play a central role in the regulation of many important cellular processes, and dysregulations at the epigenetic level could be the source of serious pathologies, such as neurological disorders affecting brain development, neurodegeneration, and intellectual disability. Despite significant technological advances for epigenetic profiling, there is still a need for a systematic understanding of how epigenetics shapes cellular circuitry, and disease pathogenesis. The development of accurate computational approaches for analyzing complex epigenetic profiles is essential for disentangling the mechanisms underlying cellular development, and the intricate interaction networks determining and sensing chromatin modifications and DNA methylation to control gene expression. In this chapter, we review the recent advances in the field of "computational epigenetics," including computational methods for processing different types of epigenetic data, prediction of chromatin states, and study of protein dynamics. We also discuss how "computational epigenetics" has complemented the fast growth in the generation of epigenetic data for uncovering the main differences and similarities at the epigenetic level between individuals and the mechanisms underlying disease onset and progression.

  10. New insights into the epigenetics of inflammatory rheumatic diseases.

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    Ballestar, Esteban; Li, Tianlu

    2017-10-01

    Over the past decade, awareness of the importance of epigenetic alterations in the pathogenesis of rheumatic diseases has grown in parallel with a general recognition of the fundamental role of epigenetics in the regulation of gene expression. Large-scale efforts to generate genome-wide maps of epigenetic modifications in different cell types, as well as in physiological and pathological contexts, illustrate the increasing recognition of the relevance of epigenetics. To date, although several reports have demonstrated the occurrence of epigenetic alterations in a wide range of inflammatory rheumatic conditions, epigenomic information is rarely used in a clinical setting. By contrast, several epigenetic biomarkers and treatments are currently in use for personalized therapies in patients with cancer. This Review highlights advances from the past 5 years in the field of epigenetics and their application to inflammatory rheumatic diseases, delineating the future lines of development for a rational use of epigenetic information in clinical settings and in personalized medicine. These advances include the identification of epipolymorphisms associated with clinical outcomes, DNA methylation as a contributor to disease susceptibility in rheumatic conditions, the discovery of novel epigenetic mechanisms that modulate disease susceptibility and the development of new epigenetic therapies.

  11. Epigenetics: A way to bridge the gap between biological fields.

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    Nicoglou, Antonine; Merlin, Francesca

    2017-12-01

    The concept of epigenetics has evolved since Waddington defined it from the late 1930s as the study of the causal mechanisms at work in development. It has become a multi-faceted notion with different meanings, depending on the disciplinary context it is used. In this article, we first analyse the transformations of the concept of epigenetics, from Waddington to contemporary accounts, in order to identify its different meanings and traditions, and to come up with a typology of epigenetics throughout its history. Second, we show on this basis that epigenetics has progressively turned its main focus from biological problems regarding development, toward issues concerning evolution. Yet, both these different epistemological aspects of epigenetics still coexist. Third, we claim that the classical opposition between epigenesis and preformationism as ways of thinking about the developmental process is part of the history of epigenetics and has contributed to its current various meanings. With these objectives in mind, we first show how Waddington introduced the term "epigenetics" in a biological context in order to solve a developmental problem, and we then build on this by presenting Nanney's, Riggs' and Holliday's definitions, which form the basis for the current conception of "molecular epigenetics". Then, we show that the evo-devo research field is where some particular uses of epigenetics have started shifting from developmental issues to evolutionary problems. We also show that epigenetics has progressively focused on the issue of epigenetic inheritance within the Extended Evolutionary Synthesis' framework. Finally, we conclude by presenting a typology of the different conceptions of epigenetics throughout time, and analyse the connections between them. We argue that, since Waddington, epigenetics, as an integrative research area, has been used to bridge the gap between different biological fields. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. The Role of Epigenetic Change in Autism Spectrum Disorders.

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    Loke, Yuk Jing; Hannan, Anthony John; Craig, Jeffrey Mark

    2015-01-01

    Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by problems with social communication, social interaction, and repetitive or restricted behaviors. ASD are comorbid with other disorders including attention deficit hyperactivity disorder, epilepsy, Rett syndrome, and Fragile X syndrome. Neither the genetic nor the environmental components have been characterized well enough to aid diagnosis or treatment of non-syndromic ASD. However, genome-wide association studies have amassed evidence suggesting involvement of hundreds of genes and a variety of associated genetic pathways. Recently, investigators have turned to epigenetics, a prime mediator of environmental effects on genomes and phenotype, to characterize changes in ASD that constitute a molecular level on top of DNA sequence. Though in their infancy, such studies have the potential to increase our understanding of the etiology of ASD and may assist in the development of biomarkers for its prediction, diagnosis, prognosis, and eventually in its prevention and intervention. This review focuses on the first few epigenome-wide association studies of ASD and discusses future directions.

  13. The role of epigenetic change in autism spectrum disorders

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    Yuk Jin eLoke

    2015-05-01

    Full Text Available Autism spectrum disorders (ASD are a heterogeneous group of neurodevelopmental disorders characterised by problems with social communication, social interaction and repetitive or restricted behaviours. ASD is comorbid with other disorders including attention deficit hyperactivity disorder, epilepsy, Rett syndrome and Fragile X syndrome. Neither the genetic nor the environmental components have been characterised well enough to aid diagnosis or treatment of non-syndromic ASD. However, genome-wide association studies have amassed evidence suggesting involvement of hundreds of genes and a variety of associated genetic pathways. Recently, investigators have turned to epigenetics, a prime mediator of environmental effects on genomes and phenotype, to characterise changes in ASD that constitute a molecular level on top of DNA sequence. Though in their infancy, such studies have the potential to increase our understanding of the aetiology of ASD and may assist in the development of biomarkers for its prediction, diagnosis, prognosis and eventually in its prevention and intervention. This review focuses on the first few epigenome-wide association studies of ASD and discusses future directions.

  14. Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior.

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    Michael K Skinner

    Full Text Available Embryonic exposure to the endocrine disruptor vinclozolin during gonadal sex determination promotes an epigenetic reprogramming of the male germ-line that is associated with transgenerational adult onset disease states. Further analysis of this transgenerational phenotype on the brain demonstrated reproducible changes in the brain transcriptome three generations (F3 removed from the exposure. The transgenerational alterations in the male and female brain transcriptomes were distinct. In the males, the expression of 92 genes in the hippocampus and 276 genes in the amygdala were transgenerationally altered. In the females, the expression of 1,301 genes in the hippocampus and 172 genes in the amygdala were transgenerationally altered. Analysis of specific gene sets demonstrated that several brain signaling pathways were influenced including those involved in axon guidance and long-term potentiation. An investigation of behavior demonstrated that the vinclozolin F3 generation males had a decrease in anxiety-like behavior, while the females had an increase in anxiety-like behavior. These observations demonstrate that an embryonic exposure to an environmental compound appears to promote a reprogramming of brain development that correlates with transgenerational sex-specific alterations in the brain transcriptomes and behavior. Observations are discussed in regards to environmental and transgenerational influences on the etiology of brain disease.

  15. HPV epigenetic mechanisms related to Oropharyngeal and Cervix cancers.

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    Di Domenico, Marina; Giovane, Giancarlo; Kouidhi, Soumaya; Iorio, Rosamaria; Romano, Maurizio; De Francesco, Francesco; Feola, Antonia; Siciliano, Camilla; Califano, Luigi; Giordano, Antonio

    2017-03-31

    Human Papilloma Virus infection is very frequent in humans and is mainly transmitted sexually. The majority of infections are transient and asymptomatic, however, if the infection persists, it can occur with a variety of injuries to skin and mucous membranes, depending on the type of HPV involved. Some types of HPV are classified as high oncogenic risk as associated with the onset of cancer. The tumors most commonly associated with HPV are cervical and oropharyngeal cancer, epigenetic mechanisms related to HPV infection include methylation changes to host and viral DNA and chromatin modification in host species. This review is focused about epigenethic mechanism, such as MiRNAs expression, related to cervix and oral cancer. Specifically it discuss about molecular markers associated to a more aggressive phenotype. In this way we will analyze genes involved in meiotic sinaptonemal complex, transcriptional factors, of orthokeratins, sinaptogirin, they are all expressed in cancer in a way not more dependent on cell differentiation but HPV-dependent.

  16. Asthma phenotypes in childhood.

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    Reddy, Monica B; Covar, Ronina A

    2016-04-01

    This review describes the literature over the past 18 months that evaluated childhood asthma phenotypes, highlighting the key aspects of these studies, and comparing these studies to previous ones in this area. Recent studies on asthma phenotypes have identified new phenotypes on the basis of statistical analyses (using cluster analysis and latent class analysis methodology) and have evaluated the outcomes and associated risk factors of previously established early childhood asthma phenotypes that are based on asthma onset and patterns of wheezing illness. There have also been investigations focusing on immunologic, physiologic, and genetic correlates of various phenotypes, as well as identification of subphenotypes of severe childhood asthma. Childhood asthma remains a heterogeneous condition, and investigations into these various presentations, risk factors, and outcomes are important since they can offer therapeutic and prognostic relevance. Further investigation into the immunopathology and genetic basis underlying childhood phenotypes is important so therapy can be tailored accordingly.

  17. Dynamic epigenetic states of maize centromeres

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    Yalin eLiu

    2015-10-01

    Full Text Available The centromere is a specialized chromosomal region identified as the major constriction, upon which the kinetochore complex is formed, ensuring accurate chromosome orientation and segregation during cell division. The rapid evolution of centromere DNA sequence and the conserved centromere function are two contradictory aspects of centromere biology. Indeed, the sole presence of genetic sequence is not sufficient for centromere formation. Various dicentric chromosomes with one inactive centromere have been recognized. It has also been found that de novo centromere formation is common on fragments in which centromeric DNA sequences are lost. Epigenetic factors play important roles in centromeric chromatin assembly and maintenance. Nondisjunction of the supernumerary B chromosome early prophase of meiosis I requires an active centromere. This review discusses recent studies in maize about genetic and epigenetic elements regulating formation and maintenance of centromere chromatin, as well as centromere behavior in meiosis.

  18. [Application of Epigenetics in Perinatal Nursing Care].

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    Chou, Hsueh-Fen; Kao, Chien-Huei; Gau, Meei-Ling

    2017-04-01

    Epigenetics is a field of biomedicine that expanded tremendously during the 1980s. Epigenetics is the study of heritable changes in gene expression independent of underlying DNA (DeoxyriboNucleic Acid) sequence, which not only affect this generation but will be passed to subsequent generations. Although conception is the critical moment for making decisions regarding gene mapping and fetal health, studies have shown that perinatal nursing care practices also affect the genetic remodeling processes and the subsequent health of the mother and her offspring. To optimize maternal-infant and the offspring health, it is important to ensure that the new mother get adequate nutrition, reduce stress levels, adopt gentle birth practices, facilitate exclusive breastfeeding, and avoid contacting toxic substances.

  19. Epigenetic Modifications of Major Depressive Disorder

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    Kathleen Saavedra

    2016-08-01

    Full Text Available Major depressive disorder (MDD is a chronic disease whose neurological basis and pathophysiology remain poorly understood. Initially, it was proposed that genetic variations were responsible for the development of this disease. Nevertheless, several studies within the last decade have provided evidence suggesting that environmental factors play an important role in MDD pathophysiology. Alterations in epigenetics mechanism, such as DNA methylation, histone modification and microRNA expression could favor MDD advance in response to stressful experiences and environmental factors. The aim of this review is to describe genetic alterations, and particularly altered epigenetic mechanisms, that could be determinants for MDD progress, and how these alterations may arise as useful screening, diagnosis and treatment monitoring biomarkers of depressive disorders.

  20. Small RNA-Mediated Epigenetic Myostatin Silencing

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    Thomas C Roberts

    2012-01-01

    Full Text Available Myostatin (Mstn is a secreted growth factor that negatively regulates muscle mass and is therefore a potential pharmacological target for the treatment of muscle wasting disorders such as Duchenne muscular dystrophy. Here we describe a novel Mstn blockade approach in which small interfering RNAs (siRNAs complementary to a promoter-associated transcript induce transcriptional gene silencing (TGS in two differentiated mouse muscle cell lines. Silencing is sensitive to treatment with the histone deacetylase inhibitor trichostatin A, and the silent state chromatin mark H3K9me2 is enriched at the Mstn promoter following siRNA transfection, suggesting epigenetic remodeling underlies the silencing effect. These observations suggest that long-term epigenetic silencing may be feasible for Mstn and that TGS is a promising novel therapeutic strategy for the treatment of muscle wasting disorders.

  1. Epigenetics of hypoxic pulmonary arterial hypertension following intrauterine growth retardation rat: epigenetics in PAH following IUGR

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    Xu Xue-Feng

    2013-02-01

    Full Text Available Abstract Background Accumulating evidence reveals that intrauterine growth retardation (IUGR can cause varying degrees of pulmonary arterial hypertension (PAH later in life. Moreover, epigenetics plays an important role in the fetal origin of adult disease. The goal of this study was to investigate the role of epigenetics in the development of PAH following IUGR. Methods The IUGR rats were established by maternal undernutrition during pregnancy. Pulmonary vascular endothelial cells (PVEC were isolated from the rat lungs by magnetic-activated cell sorting (MACS. We investigated epigenetic regulation of the endothelin-1 (ET-1 gene in PVEC of 1-day and 6-week IUGR rats, and response of IUGR rats to hypoxia. Results The maternal nutrient restriction increased the histone acetylation and hypoxia inducible factor-1α (HIF-1α binding levels in the ET-1 gene promoter of PVEC in IUGR newborn rats, and continued up to 6 weeks after birth. These epigenetic changes could result in an IUGR rat being highly sensitive to hypoxia later in life, causing more significant PAH or pulmonary vascular remodeling. Conclusions These findings suggest that epigenetics is closely associated with the development of hypoxic PAH following IUGR, further providing a new insight for improved prevention and treatment of IUGR-related PAH.

  2. Early life trauma, depression and the glucocorticoid receptor gene--an epigenetic perspective.

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    Smart, C; Strathdee, G; Watson, S; Murgatroyd, C; McAllister-Williams, R H

    2015-12-01

    Hopes to identify genetic susceptibility loci accounting for the heritability seen in unipolar depression have not been fully realized. Family history remains the 'gold standard' for both risk stratification and prognosis in complex phenotypes such as depression. Meanwhile, the physiological mechanisms underlying life-event triggers for depression remain opaque. Epigenetics, comprising heritable changes in gene expression other than alterations of the nucleotide sequence, may offer a way to deepen our understanding of the aetiology and pathophysiology of unipolar depression and optimize treatments. A heuristic target for exploring the relevance of epigenetic changes in unipolar depression is the hypothalamic-pituitary-adrenal (HPA) axis. The glucocorticoid receptor (GR) gene (NR3C1) has been found to be susceptible to epigenetic modification, specifically DNA methylation, in the context of environmental stress such as early life trauma, which is an established risk for depression later in life. In this paper we discuss the progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 gene. Difficulties with the design of these studies are also explored. Future efforts will need to comprehensively address epigenetic natural histories at the population, tissue, cell and gene levels. The complex interactions between the epigenome, genome and environment, as well as ongoing nosological difficulties, also pose significant challenges. The work that has been done so far is nevertheless encouraging and suggests potential mechanistic and biomarker roles for differential DNA methylation patterns in NR3C1 as well as novel therapeutic targets.

  3. Epigenetics and Neural developmental disorders: Washington DC, September 18 and 19, 2006.

    Science.gov (United States)

    Zhao, Xinyu; Pak, ChangHui; Smrt, Richard D; Jin, Peng

    2007-01-01

    Neural developmental disorders, such as autism, Rett Syndrome, Fragile X syndrome, and Angelman syndrome manifest during early postnatal neural development. Although the genes responsible for some of these disorders have been identified, how the mutations of these genes affect neural development is currently unclear. Emerging evidence suggest that these disorders share common underlying defects in neuronal morphology, synaptic connectivity and brain plasticity. In particular, alterations in dendritic branching and spine morphology play a central role in the pathophysiology of most mental retardation disorders, suggesting that common pathways regulating neuronal function may be affected. Epigenetic modulations, mediated by DNA methylation, RNA-associated silencing, and histone modification, can serve as an intermediate process that imprints dynamic environmental experiences on the "fixed" genome, resulting in stable alterations in phenotypes. Disturbance in epigenetic regulations can lead to inappropriate expression or silencing of genes, causing an array of multi-system disorders and neoplasias. Rett syndrome, the most common form of mental retardation in young girls, is due to l mutation of MECP2, encoding a methylated DNA binding protein that translates DNA methylation into gene repression. Angelman syndrome is due to faulty genomic imprinting or maternal mutations in UBE3A. Fragile X Syndrome, in most cases, results from the hypermethylation of FMR1 promoter, hence the loss of expression of functional FMRP protein. Autism, with its complex etiology, may have strong epigenetic link. Together, these observations strongly suggest that epigenetic mechanisms may play a critical role in brain development and etiology of related disorders. This report summarizes the scientific discussions and major conclusions from a recent conference that aimed to gain insight into the common molecular pathways affected among these disorders and discover potential therapeutic targets

  4. In search of epigenetic marks in testes and sperm cells of differentially fed boars.

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    Rémy Bruggmann

    Full Text Available In search of transmittable epigenetic marks we investigated gene expression in testes and sperm cells of differentially fed F0 boars from a three generation pig feeding experiment that showed phenotypic differences in the F2 generation. RNA samples from 8 testes of boars that received either a diet enriched in methylating micronutrients or a control diet were analyzed by microarray analysis. We found moderate differential expression between testes of differentially fed boars with a high FDR of 0.82 indicating that most of the differentially expressed genes were false positives. Nevertheless, we performed a pathway analysis and found disparate pathway maps of development_A2B receptor: action via G-protein alpha s, cell adhesion_Tight junctions and cell adhesion_Endothelial cell contacts by junctional mechanisms which show inconclusive relation to epigenetic inheritance. Four RNA samples from sperm cells of these differentially fed boars were analyzed by RNA-Seq methodology. We found no differential gene expression in sperm cells of the two groups (adjusted P-value>0.05. Nevertheless, we also explored gene expression in sperm by a pathway analysis showing that genes were enriched for the pathway maps of bacterial infections in cystic fibrosis (CF airways, glycolysis and gluconeogenesis p.3 and cell cycle_Initiation of mitosis. Again, these pathway maps are miscellaneous without an obvious relationship to epigenetic inheritance. It is concluded that the methylating micronutrients moderately if at all affects RNA expression in testes of differentially fed boars. Furthermore, gene expression in sperm cells is not significantly affected by extensive supplementation of methylating micronutrients and thus RNA molecules could not be established as the epigenetic mark in this feeding experiment.

  5. Dietary regulation of developmental programming in ruminants: epigenetic modifications in the germline.

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    Sinclair, K D; Karamitri, A; Gardner, D S

    2010-01-01

    Ruminants have been utilised extensively to investigate the developmental origins of health and disease, with the sheep serving as the model species of choice to complement dietary studies in the rat and mouse. Surprisingly few studies, however, have investigated delayed effects of maternal undernutrition during pregnancy on adult offspring health and a consistent phenotype, together with underlying mechanistic pathways, has not emerged. Nevertheless, when broad consideration is given to all studies with ruminants it is apparent that interventions that are initiated very early in gestation, and/or prior to conception, lead to greater effects on adult physiology than those that are specifically targeted to late gestation. Effects induced following dietary interventions at the earliest stages of mammalian development have been shown to arise as a consequence of alterations to key epigenetic processes that occur in germ cells and pluripotent embryonic cells. Currently, our understanding of epigenetic programming in the germline is greatest for the mouse, and is considered in detail in this article together with what is known in ruminants. This species imbalance, however, looks set to change as fully annotated genomic maps are developed for domesticated large animal species, and with the advent of 'next-generation' DNA sequencing technologies that have the power to globally map the epigenome at single-base-pair resolution. These developments would help to address such issues as sexually dimorphic epigenetic alterations to DNA methylation that have been found to arise following dietary restrictions during the peri-conceptional period, the effects of paternal nutritional status on epigenetic programming through the germline, and transgenerational studies where, in future, greater emphasis in domesticated ruminants should be placed on traits of agricultural importance.

  6. Derangement of a factor upstream of RARalpha triggers the repression of a pleiotropic epigenetic network.

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    Francesca Corlazzoli

    Full Text Available Chromatin adapts and responds to extrinsic and intrinsic cues. We hypothesize that inheritable aberrant chromatin states in cancer and aging are caused by genetic/environmental factors. In previous studies we demonstrated that either genetic mutations, or loss, of retinoic acid receptor alpha (RARalpha, can impair the integration of the retinoic acid (RA signal at the chromatin of RA-responsive genes downstream of RARalpha, and can lead to aberrant repressive chromatin states marked by epigenetic modifications. In this study we tested whether the mere interference with the availability of RA signal at RARalpha, in cells with an otherwise functional RARalpha, can also induce epigenetic repression at RA-responsive genes downstream of RARalpha.To hamper the availability of RA at RARalpha in untransformed human mammary epithelial cells, we targeted the cellular RA-binding protein 2 (CRABP2, which transports RA from the cytoplasm onto the nuclear RARs. Stable ectopic expression of a CRABP2 mutant unable to enter the nucleus, as well as stable knock down of endogenous CRABP2, led to the coordinated transcriptional repression of a few RA-responsive genes downstream of RARalpha. The chromatin at these genes acquired an exacerbated repressed state, or state "of no return". This aberrant state is unresponsive to RA, and therefore differs from the physiologically repressed, yet "poised" state, which is responsive to RA. Consistent with development of homozygosis for epigenetically repressed loci, a significant proportion of cells with a defective CRABP2-mediated RA transport developed heritable phenotypes indicative of loss of function.Derangement/lack of a critical factor necessary for RARalpha function induces epigenetic repression of a RA-regulated gene network downstream of RARalpha, with major pleiotropic biological outcomes.

  7. Microbiome, inflammation, epigenetic alterations, and mental diseases.

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    Alam, Reza; Abdolmaleky, Hamid M; Zhou, Jin-Rong

    2017-09-01

    Major mental diseases such as autism, bipolar disorder, schizophrenia, and major depressive disorder are debilitating illnesses with complex etiologies. Recent findings show that the onset and development of these illnesses cannot be well described by the one-gene; one-disease approach. Instead, their clinical presentation is thought to result from the regulative interplay of a large number of genes. Even though the involvement of many genes are likely, up regulating and activation or down regulation and silencing of these genes by the environmental factors play a crucial role in contributing to their pathogenesis. Much of this interplay may be moderated by epigenetic changes. Similar to genetic mutations, epigenetic modifications such as DNA methylation, histone modifications, and RNA interference can influence gene expression and therefore may cause behavioral and neuronal changes observed in mental disorders. Environmental factors such as diet, gut microbiota, and infections have significant role in these epigenetic modifications. Studies show that bioactive nutrients and gut microbiota can alter either DNA methylation and histone signatures through a variety of mechanisms. Indeed, microbes within the human gut may play a significant role in the regulation of various elements of "gut-brain axis," via their influence on inflammatory cytokines and production of antimicrobial peptides that affect the epigenome through their involvement in generating short chain fatty acids, vitamin synthesis, and nutrient absorption. In addition, they may participate in-gut production of many common neurotransmitters. In this review we will consider the potential interactions of diet, gastrointestinal microbiome, inflammation, and epigenetic alterations in psychiatric disorders. © 2017 Wiley Periodicals, Inc.

  8. Noncoding Elements: Evolution and Epigenetic Regulation

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    Seridi, Loqmane

    2016-03-09

    When the human genome project was completed, it revealed a surprising result. 98% of the genome did not code for protein of which more than 50% are repeats— later known as ”Junk DNA”. However, comparative genomics unveiled that many noncoding elements are evolutionarily constrained; thus luckily to have a role in genome stability and regulation. Though, their exact functions remained largely unknown. Several large international consortia such as the Functional Annotation of Mammalian Genomes (FANTOM) and the Encyclopedia of DNA Elements (ENCODE) were set to understand the structure and the regulation of the genome. Specifically, these endeavors aim to measure and reveal the transcribed components and functional elements of the genome. One of the most the striking findings of these efforts is that most of the genome is transcribed, including non-conserved noncoding elements and repeat elements. Specifically, we investigated the evolution and epigenetic properties of noncoding elements. 1. We compared genomes of evolutionarily distant species and showed the ubiquity of constrained noncoding elements in metazoa. 2. By integrating multi-omic data (such as transcriptome, nucleosome profiling, histone modifications), I conducted a comprehensive analysis of epigenetic properties (chromatin states) of conserved noncoding elements in insects. We showed that those elements have distinct and protective sequence features, undergo dynamic epigenetic regulation, and appear to be associated with the structural components of the chromatin, replication origins, and nuclear matrix. 3. I focused on the relationship between enhancers and repetitive elements. Using Cap Analysis of Gene Expression (CAGE) and RNASeq, I compiled a full catalog of active enhancers (a class of noncoding elements) during myogenesis of human primary cells of healthy donors and donors affected by Duchenne muscular dystrophy (DMD). Comparing the two time-courses, a significant change in the epigenetic

  9. Bisphenol A in Reproduction: Epigenetic Effects.

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    Chianese, Rosanna; Troisi, Jacopo; Richards, Sean; Scafuro, Marika; Fasano, Silvia; Guida, Maurizio; Pierantoni, Riccardo; Meccariello, Rosaria

    2018-02-21

    Bisphenol A (BPA) is an endocrine disrupting chemical widely used in the manufacture of polycarbonate plastic and epoxy resin to produce a multitude of consumer products, food and drink containers, and medical devices. BPA is similar to estradiol in structure and thus interferes in steroid signalling with different outcomes on reproductive health depending on doses, life stage, mode, and timing of exposure. In this respect, it has an emerging and controversial role as a "reproductive toxicant" capable of inducing short and long-term effects including the modulation of gene expression through epigenetic modification (i.e. methylation of CpG islands, histone modifications and production of non-coding RNA) with direct and trans-generational effects on exposed organisms and their offspring, respectively. This review provides an overview about BPA effects on reproductive health and aims to summarize the epigenetic effects of BPA in male and female reproduction. BPA exerts epigenetic effects in both male and female reproduction. In males, BPA affects spermatogenesis and sperm quality and possible trans-generational effects on the reproductive ability of the offspring. In females, BPA affects ovary, embryo development, and gamete quality for successful in vivo and in vitro fertilization (IVF). The exact mechanisms of BPA-mediated effects in reproduction are not fully understood; however, the environmental exposure to BPA - especially in fetal and neonatal period - deserves attention to preserve the reproductive ability in both sexes and to reduce the epigenetic risk for the offspring. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Epigenetic regulation in Autism spectrum disorder

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    Sraboni Chaudhury

    2016-12-01

    Full Text Available Autism spectrum disorder (ASD is a neurodevelopmental disorder characterized by an impaired social communication skill and often results in repetitive, stereotyped behavior which is observed in children during the first few years of life. Other characteristic of this disorder includes language disabilities, difficulties in sensory integration, lack of reciprocal interactions and in some cases, cognitive delays. One percentage of the general population is affected by ASD and is four times more common in boys than girls. There are hundreds of genes, which has been identified to be associated with ASD etiology. However it remains difficult to comprehend our understanding in defining the genetic architecture necessary for complete exposition of its pathophysiology. Seeing the complexity of the disease, it is important to adopt a multidisciplinary approach which should not only focus on the “genetics” of autism but also on epigenetics, transcriptomics, immune system disruption and environmental factors that could all impact the pathogenesis of the disease. As environmental factors also play a key role in regulating the trigger of ASD, the role of chromatin remodeling and DNA methylation has started to emerge. Such epigenetic modifications directly link molecular regulatory pathways and environmental factors, which might be able to explain some aspects of complex disorders like ASD. The present review will focus on the role of epigenetic regulation in defining the underlying cause for ASD

  11. Parental tobacco smoke exposure: Epigenetics and the ...

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    Epigenetic programming is an important mechanism underlying the Developmental Origins of Health and Disease (DOHaD). Much of the research in this area has focused on maternal nutrition. Parental smoking has emerged as a prime example of how exposure to environmental toxicants during the preconceptional and in utero periods can have long-term effects on offspring health, and the role of the epigenome in these effects. Maternal smoking and exposure to second-hand smoke during pregnancy result in lower birth weight of offspring, and there is now clear evidence that these offspring are at elevated risk for overweight/obesity, type-2 diabetes, respiratory effects during adolescence and adulthood, and may be programmed for increased risk of nicotine addiction. Epigenetic analyses of placenta, cord blood and offspring buccal cells have consistently revealed altered DNA methylation of genes involved in developmental processes and xenobiotic metabolism, and these epigenetic changes are persistent. Animal studies with cigarette smoke and nicotine support these findings. Paternal preconceptional smoking has been positively related to childhood cancers, potentially linked to changes in the sperm epigenome. Germ cell specification and preimplantation development are periods of widespread erasure and reprogramming of DNA methylation, and as such are likely to be sensitive periods for environmental effects on the epigenome. Exposure to tobacco smoke during gametogenesis and in

  12. Epigenetic regulation of axon and dendrite growth

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    Ephraim F Trakhtenberg

    2012-03-01

    Full Text Available Neuroregenerative therapies for central nervous system (CNS injury, neurodegenerative disease, or stroke require axons of damaged neurons to grow and reinnervate their targets. However, mature mammalian CNS neurons do not regenerate their axons, limiting recovery in these diseases (Yiu and He, 2006. CNS’ regenerative failure may be attributable to the development of an inhibitory CNS environment by glial-associated inhibitory molecules (Yiu and He, 2006, and by various cell-autonomous factors (Sun and He, 2010. Intrinsic axon growth ability also declines developmentally (Li et al., 1995; Goldberg et al., 2002; Bouslama-Oueghlani et al., 2003; Blackmore and Letourneau, 2006 and is dependent on transcription (Moore et al., 2009. Although neurons’ intrinsic capacity for axon growth may depend in part on the panoply of expressed transcription factors (Moore and Goldberg, 2011, epigenetic factors such as the accessibility of DNA and organization of chromatin are required for downstream genes to be transcribed. Thus a potential approach to overcoming regenerative failure focuses on the epigenetic mechanisms regulating regenerative gene expression in the CNS. Here we review molecular mechanisms regulating the epigenetic state of DNA through chromatin modifications, their implications for regulating axon and dendrite growth, and important new directions for this field of study.

  13. Epigenetic Basis of Neuronal and Synaptic Plasticity.

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    Karpova, Nina N; Sales, Amanda J; Joca, Samia R

    2017-01-01

    Neuronal network and plasticity change as a function of experience. Altered neural connectivity leads to distinct transcriptional programs of neuronal plasticity-related genes. The environmental challenges throughout life may promote long-lasting reprogramming of gene expression and the development of brain disorders. The modifications in neuronal epigenome mediate gene-environmental interactions and are required for activity-dependent regulation of neuronal differentiation, maturation and plasticity. Here, we highlight the latest advances in understanding the role of the main players of epigenetic machinery (DNA methylation and demethylation, histone modifications, chromatin-remodeling enzymes, transposons, and non-coding RNAs) in activity-dependent and long- term neural and synaptic plasticity. The review focuses on both the transcriptional and post-transcriptional regulation of gene expression levels, including the processes of promoter activation, alternative splicing, regulation of stability of gene transcripts by natural antisense RNAs, and alternative polyadenylation. Further, we discuss the epigenetic aspects of impaired neuronal plasticity and the pathogenesis of neurodevelopmental (Rett syndrome, Fragile X Syndrome, genomic imprinting disorders, schizophrenia, and others), stressrelated (mood disorders) and neurodegenerative Alzheimer's, Parkinson's and Huntington's disorders. The review also highlights the pharmacological compounds that modulate epigenetic programming of gene expression, the potential treatment strategies of discussed brain disorders, and the questions that should be addressed during the development of effective and safe approaches for the treatment of brain disorders.

  14. Titration and hysteresis in epigenetic chromatin silencing

    International Nuclear Information System (INIS)

    Dayarian, Adel; Sengupta, Anirvan M

    2013-01-01

    Epigenetic mechanisms of silencing via heritable chromatin modifications play a major role in gene regulation and cell fate specification. We consider a model of epigenetic chromatin silencing in budding yeast and study the bifurcation diagram and characterize the bistable and the monostable regimes. The main focus of this paper is to examine how the perturbations altering the activity of histone modifying enzymes affect the epigenetic states. We analyze the implications of having the total number of silencing proteins, given by the sum of proteins bound to the nucleosomes and the ones available in the ambient, to be constant. This constraint couples different regions of chromatin through the shared reservoir of ambient silencing proteins. We show that the response of the system to perturbations depends dramatically on the titration effect caused by the above constraint. In particular, for a certain range of overall abundance of silencing proteins, the hysteresis loop changes qualitatively with certain jump replaced by continuous merger of different states. In addition, we find a nonmonotonic dependence of gene expression on the rate of histone deacetylation activity of Sir2. We discuss how these qualitative predictions of our model could be compared with experimental studies of the yeast system under anti-silencing drugs. (paper)

  15. Robotic liquid handling and automation in epigenetics.

    Science.gov (United States)

    Gaisford, Wendy

    2012-10-01

    Automated liquid-handling robots and high-throughput screening (HTS) are widely used in the pharmaceutical industry for the screening of large compound libraries, small molecules for activity against disease-relevant target pathways, or proteins. HTS robots capable of low-volume dispensing reduce assay setup times and provide highly accurate and reproducible dispensing, minimizing variation between sample replicates and eliminating the potential for manual error. Low-volume automated nanoliter dispensers ensure accuracy of pipetting within volume ranges that are difficult to achieve manually. In addition, they have the ability to potentially expand the range of screening conditions from often limited amounts of valuable sample, as well as reduce the usage of expensive reagents. The ability to accurately dispense lower volumes provides the potential to achieve a greater amount of information than could be otherwise achieved using manual dispensing technology. With the emergence of the field of epigenetics, an increasing number of drug discovery companies are beginning to screen compound libraries against a range of epigenetic targets. This review discusses the potential for the use of low-volume liquid handling robots, for molecular biological applications such as quantitative PCR and epigenetics.

  16. Testicular cancer from diagnosis to epigenetic factors

    Science.gov (United States)

    Boccellino, Mariarosaria; Vanacore, Daniela; Zappavigna, Silvia; Cavaliere, Carla; Rossetti, Sabrina; D’Aniello, Carmine; Chieffi, Paolo; Amler, Evzen; Buonerba, Carlo; Di Lorenzo, Giuseppe; Di Franco, Rossella; Izzo, Alessandro; Piscitelli, Raffaele; Iovane, Gelsomina; Muto, Paolo; Botti, Gerardo; Perdonà, Sisto; Caraglia, Michele; Facchini, Gaetano

    2017-01-01

    Testicular cancer (TC) is one of the most common neoplasms that occurs in male and includes germ cell tumors (GCT), sex cord-gonadal stromal tumors and secondary testicular tumors. Diagnosis of TC involves the evaluation of serum tumor markers alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase, but clinically several types of immunohistochemical markers are more useful and more sensitive in GCT, but not in teratoma. These new biomarkers are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency-related cells but not in normal adult germ cells and they include PLAP, OCT3/4 (POU5F1), NANOG, SOX2, REX1, AP-2γ (TFAP2C) and LIN28. Gene expression in GCT is regulated, at least in part, by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation. There are different epigenetic modifications in TG-subtypes that reflect the normal developmental switch in primordial germ cells from an under- to normally methylated genome. The main purpose of this review is to illustrate the findings of recent investigations in the classification of male genital organs, the discoveries in the use of prognostic and diagnostic markers and the epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and microRNAs (miRNAs). PMID:29262668

  17. Epigenetic analysis of childhood acute lymphoblastic leukemia.

    Science.gov (United States)

    Dunwell, Thomas L; Hesson, Luke B; Pavlova, Tatiana; Zabarovska, Veronika; Kashuba, Vladimir; Catchpoole, Daniel; Chiaramonte, Raffaella; Brini, Anna T; Griffiths, Mike; Maher, Eamonn R; Zabarovsky, Eugene; Latif, Farida

    2009-04-01

    We used a chromosome 3 wide NotI microarray for identification of epigenetically inactivated genes in childhood acute lymphoblastic leukemia (ALL). Three novel genes demonstrated frequent methylation in childhood ALL. PPP2R3A (protein phosphatase 2, regulatory subunit B", alpha) was frequently methylated in T (69%) and B (82%)-ALL. Whilst FBLN2 (fibulin 2) and THRB (thyroid hormone receptor, beta) showed frequent methylation in B-ALL (58%; 56% respectively), but were less frequently methylated in T-ALL (17% for both genes). Recently it was demonstrated that BNC1 (Basonuclin 1) and MSX1 (msh homeobox 1) were frequently methylated across common epithelial cancers. In our series of childhood ALL BNC1 was frequently methylated in both T (77%) and B-ALL (79%), whilst MSX1 showed T-ALL (25%) specific methylation. The methylation of the above five genes was cancer specific and expression of the genes could be restored in methylated leukemia cell lines treated with 5-aza-2'-deoxycytidine. This is the first report demonstrating frequent epigenetic inactivation of PPP2R3A, FBLN2, THRB, BNC1 and MSX1 in leukemia. The identification of frequently methylated genes showing cancer specific methylation will be useful in developing early cancer detection screens and for targeted epigenetic therapies.

  18. Epigenetic and epistatic interactions between serotonin transporter and brain-derived neurotrophic factor genetic polymorphism: insights in depression.

    Science.gov (United States)

    Ignácio, Z M; Réus, G Z; Abelaira, H M; Quevedo, J

    2014-09-05

    Epidemiological studies have shown significant results in the interaction between the functions of brain-derived neurotrophic factor (BDNF) and 5-HT in mood disorders, such as major depressive disorder (MDD). The latest research has provided convincing evidence that gene transcription of these molecules is a target for epigenetic changes, triggered by stressful stimuli that starts in early childhood and continues throughout life, which are subsequently translated into structural and functional phenotypes culminating in depressive disorders. The short variants of 5-HTTLPR and BDNF-Met are seen as forms which are predisposed to epigenetic aberrations, which leads individuals to a susceptibility to environmental adversities, especially when subjected to stress in early life. Moreover, the polymorphic variants also feature epistatic interactions in directing the functional mechanisms elicited by stress and underlying the onset of depressive disorders. Also emphasized are works which show some mediators between stress and epigenetic changes of the 5-HTT and BDNF genes, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cAMP response element-binding protein (CREB), which is a cellular transcription factor. Both the HPA axis and CREB are also involved in epistatic interactions between polymorphic variants of 5-HTTLPR and Val66Met. This review highlights some research studying changes in the epigenetic patterns intrinsic to genes of 5-HTT and BDNF, which are related to lifelong environmental adversities, which in turn increases the risks of developing MDD. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Epigenetic modulation of dental pulp stem cells: implications for regenerative endodontics.

    Science.gov (United States)

    Duncan, H F; Smith, A J; Fleming, G J P; Cooper, P R

    2016-05-01

    Dental pulp stem cells (DPSCs) offer significant potential for use in regenerative endodontics, and therefore, identifying cellular regulators that control stem cell fate is critical to devising novel treatment strategies. Stem cell lineage commitment and differentiation are regulated by an intricate range of host and environmental factors of which epigenetic influence is considered vital. Epigenetic modification of DNA and DNA-associated histone proteins has been demonstrated to control cell phenotype and regulate the renewal and pluripotency of stem cell populations. The activities of the nuclear enzymes, histone deacetylases, are increasingly being recognized as potential targets for pharmacologically inducing stem cell differentiation and dedifferentiation. Depending on cell maturity and niche in vitro, low concentration histone deacetylase inhibitor (HDACi) application can promote dedifferentiation of several post-natal and mouse embryonic stem cell populations and conversely increase differentiation and accelerate mineralization in DPSC populations, whilst animal studies have shown an HDACi-induced increase in stem cell marker expression during organ regeneration. Notably, both HDAC and DNA methyltransferase inhibitors have also been demonstrated to dramatically increase the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) for use in regenerative therapeutic procedures. As the regulation of cell fate will likely remain the subject of intense future research activity, this review aims to describe the current knowledge relating to stem cell epigenetic modification, focusing on the role of HDACi on alteration of DPSC phenotype, whilst presenting the potential for therapeutic application as part of regenerative endodontic regimens. © 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd.

  20. Epigenetic features of testicular germ cell tumours in relation to epigenetic characteristics of foetal germ cells

    DEFF Research Database (Denmark)

    Kristensen, Dina Graae; Skakkebæk, Niels E; Rajpert-De Meyts, Ewa

    2013-01-01

    in humans. However, the common precursor of testicular cancers- the carcinoma in situ (CIS) cell- is thought to be an arrested foetal germ cell. Therefore studies of CIS cells may leverage information on human foetal germ cell development and, in particular, when neoplastic transformation is initiated....... In this review, we will focus on current knowledge of the epigenetics of CIS cells and relate it to the epigenetic changes occurring in early developing germ cells of mice during specification, migration and colonization. We will focus on DNA methylation and some of the best studied histone modifications like H3...... event in the initiation of testicular germ cell cancer. Even though only sparse information is available on epigenetic cues in human foetal germ cells, these indicate that the developmental patterns differ from the findings in mice and emphasize the need for further studies of foetal germ cell...