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  1. Chemical Inhibitors of Epigenetic Methyllysine Reader Proteins.

    Science.gov (United States)

    Milosevich, Natalia; Hof, Fraser

    2016-03-22

    Protein methylation is a common post-translational modification with diverse biological functions. Methyllysine reader proteins are increasingly a focus of epigenetics research and play important roles in regulating many cellular processes. These reader proteins are vital players in development, cell cycle regulation, stress responses, oncogenesis, and other disease pathways. The recent emergence of a small number of chemical inhibitors for methyllysine reader proteins supports the viability of these proteins as targets for drug development. This article introduces the biochemistry and biology of methyllysine reader proteins, provides an overview of functions for those families of readers that have been targeted to date (MBT, PHD, tudor, and chromodomains), and reviews the development of synthetic agents that directly block their methyllysine reading functions. PMID:26650180

  2. Influence of environmental chemicals on epigenetic programming and its applicability in human health risk assessment.

    Science.gov (United States)

    The field of epigenetics is rapidly evolving in response to the growing concern that heritable changes in gene expression may be involved in chemically-mediated adverse health outcomes, such as cancer. Although human and animal studies have shown a strong involvement of epigeneti...

  3. Genetic, environmental, and epigenetic factors involved in CAKUT.

    Science.gov (United States)

    Nicolaou, Nayia; Renkema, Kirsten Y; Bongers, Ernie M H F; Giles, Rachel H; Knoers, Nine V A M

    2015-12-01

    Congenital anomalies of the kidney and urinary tract (CAKUT) refer to a spectrum of structural renal malformations and are the leading cause of end-stage renal disease in children. The genetic diagnosis of CAKUT has proven to be challenging due to genetic and phenotypic heterogeneity and incomplete genetic penetrance. Monogenic causes of CAKUT have been identified using different approaches, including single gene screening, and gene panel and whole exome sequencing. The majority of the identified mutations, however, lack substantial evidence to support a pathogenic role in CAKUT. Copy number variants or single nucleotide variants that are associated with CAKUT have also been identified. Numerous studies support the influence of epigenetic and environmental factors on kidney development and the natural history of CAKUT, suggesting that the pathogenesis of this syndrome is multifactorial. In this Review we describe the current knowledge regarding the genetic susceptibility underlying CAKUT and the approaches used to investigate the genetic basis of CAKUT. We outline the associated environmental risk factors and epigenetic influences on CAKUT and discuss the challenges and strategies used to fully address the involvement and interplay of these factors in the pathogenesis of the disease. PMID:26281895

  4. Epigenetic Effects of Environmental Chemicals Bisphenol A and Phthalates

    Directory of Open Access Journals (Sweden)

    Steven Shoei-Lung Li

    2012-08-01

    Full Text Available The epigenetic effects on DNA methylation, histone modification, and expression of non-coding RNAs (including microRNAs of environmental chemicals such as bisphenol A (BPA and phthalates have expanded our understanding of the etiology of human complex diseases such as cancers and diabetes. Multiple lines of evidence from in vitro and in vivo models have established that epigenetic modifications caused by in utero exposure to environmental toxicants can induce alterations in gene expression that may persist throughout life. Epigenetics is an important mechanism in the ability of environmental chemicals to influence health and disease, and BPA and phthalates are epigenetically toxic. The epigenetic effect of BPA was clearly demonstrated in viable yellow mice by decreasing CpG methylation upstream of the Agouti gene, and the hypomethylating effect of BPA was prevented by maternal dietary supplementation with a methyl donor like folic acid or the phytoestrogen genistein. Histone H3 was found to be trimethylated at lysine 27 by BPA effect on EZH2 in a human breast cancer cell line and mice. BPA exposure of human placental cell lines has been shown to alter microRNA expression levels, and specifically, miR-146a was strongly induced by BPA treatment. In human breast cancer MCF7 cells, treatment with the phthalate BBP led to demethylation of estrogen receptor (ESR1 promoter-associated CpG islands, indicating that altered ESR1 mRNA expression by BBP is due to aberrant DNA methylation. Maternal exposure to phthalate DEHP was also shown to increase DNA methylation and expression levels of DNA methyltransferases in mouse testis. Further, some epigenetic effects of BPA and phthalates in female rats were found to be transgenerational. Finally, the available new technologies for global analysis of epigenetic alterations will provide insight into the extent and patterns of alterations between human normal and diseased tissues.

  5. Involvement of genetic and epigenetic steps in radiation carcinogenesis

    International Nuclear Information System (INIS)

    Radiation carcinogenic risk prediction requires fundamental mechanistic assumptions about relationships between dose, DNA damage in certain regions leukemogenesis in the mouse may be viewed as specific chromosome aberration. Model of transformation by radiation induced chromosome aberrations is analyzed. Model is able to fit dose-response data for cell neoplastic transformation and cancer incidence in rodents. Alternative model is studied in which an induction of neoplastic phenotype is considered as delayed indirect effects of radiation. Initiating event is triggered by an epigenetic genomic modifications and represents a change in the program of cell senescence due to in part functional inactivation of senescence gene(s). The following possibilities are modeled. Radiation induces an unstable cell phenotype which reverses to normal one after many cell generations. Induction of highly unstable phenotype. Altered cells are assumed to acquire ability to generate new phenotype. Induction of stable alterations of cell phenotype following irradiation. Model suggests an essential role for selection of cells resistant to growth inhibition signals during promotion in vivo or sub culturing in vitro for development of cancer cell clones. Appearance the damage at specific sequences during the oncogenic transformation are predicted. The model fits data on dynamics of X-ray transformation of rodent cells in culture. Results are in qualitative agreement with data on radiation induced mouse mammary cancer and delayed expression of p53 mutations. The changes in hetero-chromating may cause significant changes in the control of gene expression during oncogeny. Chromatin structural alterations which are observed for chemical and viral transformation are expected to be an earliest and general phenomenon for radiation carcinogenesis. (authors)

  6. Involvement of epigenetic modifiers in the pathogenesis of testicular dysgenesis and germ cell cancer

    DEFF Research Database (Denmark)

    Lawaetz, Andreas C.; Almstrup, Kristian

    2015-01-01

    cell is a fetal germ cell that has been arrested during development due to testicular dysgenesis. CIS cells retain a fetal and open chromatin structure, and recently several epigenetic modifiers have been suggested to be involved in testicular dysgenesis in mice. We here review the possible involvement...... of epigenetic modifiers with a focus on jumonji C enzymes in the development of testicular dysgenesis and germ cell cancer in men....

  7. Ochratoxin A carcinogenicity involves a complex network of epigenetic mechanisms.

    Science.gov (United States)

    Marin-Kuan, Maricel; Cavin, Christophe; Delatour, Thierry; Schilter, Benoît

    2008-08-01

    Ochratoxin A (OTA) is a mycotoxin occurring in a wide range of food products. Because of the limitation of human epidemiological data, the safety significance of OTA in food has to rely on animal data, with renal toxicity and carcinogenicity being considered the pivotal effects. The elucidation of the mechanism of action would improve the use of experimental animal data for risk assessment. Direct genotoxicity versus epigenetic mechanisms appears to be a key question. In the present review, the increasingly documented epigenetic cellular effects of OTA and their potential toxicological relevance are discussed. The information available suggests that OTA is unlikely to act through a single, well-defined mechanism of action. Instead, it is proposed that a network of interacting epigenetic mechanisms, including protein synthesis inhibition, oxidative stress and the activation of specific cell signalling pathways, is responsible for OTA carcinogenicity. From a risk assessment perspective, it has to be noted that the mechanisms proposed above depend mainly upon gene expression and enzyme activation, and are, therefore, likely to be thresholded. PMID:18649906

  8. 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...

  9. Variation in genes involved in epigenetic processes offers insights into tropically adapted cattle diversity.

    Science.gov (United States)

    Porto-Neto, Laercio R; Fortes, Marina R S; McWilliam, Sean M; Lehnert, Sigrid A; Reverter, Antonio

    2014-01-01

    We evaluated the relevance of the BovineHD Illumina SNP chip with respect to genes involved in epigenetic processes. Genotypes for 729,068 SNP on two tropical cattle breeds of Australia were used: Brahman (n = 2112) and Tropical Composite (n = 2550). We used data mining approaches to compile a list of bovine protein-coding genes involved in epigenetic processes. These genes represent 9 functional categories that contain between one (histone demethylases) and 99 (chromatin remodeling factors) genes. A total of 3091 SNP mapped to positions within 3000 bp of the 193 coding regions of those genes, including 113 SNP in transcribed regions, 2738 in intronic regions and 240 in up- or down-stream regions. For all these SNP categories, we observed differences in the allelic frequencies between Brahman and Tropical Composite cattle. These differences were larger than those observed for the entire set of 729,068 SNP (P = 1.79 x 10(-5)). A multidimensional scaling analysis using only the 113 SNP in transcribed regions allowed for the separation of the two populations and this separation was comparable to the one obtained with a random set of 113 SNP (Principal Component 1 r (2) > 0.84). To further characterize the differences between the breeds we defined a gene-differentiation metric based on the average genotypic frequencies of SNP connected to each gene and compared both cattle populations. The 10% most differentiated genes were distributed across 10 chromosomes, with significant (P < 0.05) enrichment on BTA 3 and 10. The 10% most conserved genes were located in 12 chromosomes. We conclude that there is variation between cattle populations in genes connected to epigenetic processes, and this variation can be used to differentiate cattle breeds. More research is needed to fully characterize the use of these SNP and its potential as means to further our understanding of biological variation and epigenetic processes. PMID:24795751

  10. Variation in genes involved in epigenetic processes offers insights into tropically adapted cattle diversity

    Directory of Open Access Journals (Sweden)

    Laercio R Porto-Neto

    2014-04-01

    Full Text Available We evaluated the relevance of the BovineHD Illumina SNP chip with respect to genes involved in epigenetic processes. Genotypes for 729,068 SNP on two tropical cattle breeds of Australia were used: Brahman (n = 2,112 and Tropical Composite (n = 2,550. We used data mining approaches to compile a list of bovine protein-coding genes involved in epigenetic processes. These genes represent 9 functional categories that contain between one (histone demethylases and 99 (chromatin remodelling factors genes. A total of 3,091 SNP mapped to positions within 3,000 bp of the 193 coding regions of those genes, including 113 SNP in transcribed regions, 2,738 in intronic regions and 240 in up- or down-stream regions. For all these SNP categories, we observed differences in the allelic frequencies between Brahman and Tropical Composite cattle. These differences were larger than those observed for the entire set of 729,068 SNP (P = 1.79 x 10-5. A multidimensional scaling analysis using only the 113 SNP in transcribed regions allowed for the separation of the two populations and this separation was comparable to the one obtained with a random set of 113 SNP (Principal Component 1 r2 > 0.84. To further characterise the differences between the breeds we defined a gene-differentiation metric based on the average genotypic frequencies of SNP connected to each gene and compared both cattle populations. The 10% most differentiated genes were distributed across 10 chromosomes, with significant (P < 0.05 enrichment on BTA 3 and 10. The 10% most conserved genes were located in 12 chromosomes. We conclude that there is variation between cattle populations in genes connected to epigenetic processes, and this variation can be used to differentiate cattle breeds. More research is needed to fully characterise the use of these SNP and its potential as means to further our understanding of biological variation and epigenetic processes.

  11. Transcriptional, epigenetic and retroviral signatures identify regulatory regions involved in hematopoietic lineage commitment.

    Science.gov (United States)

    Romano, Oriana; Peano, Clelia; Tagliazucchi, Guidantonio Malagoli; Petiti, Luca; Poletti, Valentina; Cocchiarella, Fabienne; Rizzi, Ermanno; Severgnini, Marco; Cavazza, Alessia; Rossi, Claudia; Pagliaro, Pasqualepaolo; Ambrosi, Alessandro; Ferrari, Giuliana; Bicciato, Silvio; De Bellis, Gianluca; Mavilio, Fulvio; Miccio, Annarita

    2016-01-01

    Genome-wide approaches allow investigating the molecular circuitry wiring the genetic and epigenetic programs of human somatic stem cells. Hematopoietic stem/progenitor cells (HSPC) give rise to the different blood cell types; however, the molecular basis of human hematopoietic lineage commitment is poorly characterized. Here, we define the transcriptional and epigenetic profile of human HSPC and early myeloid and erythroid progenitors by a combination of Cap Analysis of Gene Expression (CAGE), ChIP-seq and Moloney leukemia virus (MLV) integration site mapping. Most promoters and transcripts were shared by HSPC and committed progenitors, while enhancers and super-enhancers consistently changed upon differentiation, indicating that lineage commitment is essentially regulated by enhancer elements. A significant fraction of CAGE promoters differentially expressed upon commitment were novel, harbored a chromatin enhancer signature, and may identify promoters and transcribed enhancers driving cell commitment. MLV-targeted genomic regions co-mapped with cell-specific active enhancers and super-enhancers. Expression analyses, together with an enhancer functional assay, indicate that MLV integration can be used to identify bona fide developmentally regulated enhancers. Overall, this study provides an overview of transcriptional and epigenetic changes associated to HSPC lineage commitment, and a novel signature for regulatory elements involved in cell identity. PMID:27095295

  12. Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases.

    Science.gov (United States)

    Ruchat, Stephanie-May; Houde, Andrée-Anne; Voisin, Grégory; St-Pierre, Julie; Perron, Patrice; Baillargeon, Jean-Patrice; Gaudet, Daniel; Hivert, Marie-France; Brisson, Diane; Bouchard, Luigi

    2013-09-01

    Offspring exposed to gestational diabetes mellitus (GDM) have an increased risk for chronic diseases, and one promising mechanism for fetal metabolic programming is epigenetics. Therefore, we postulated that GDM exposure impacts the offspring's methylome and used an epigenomic approach to explore this hypothesis. Placenta and cord blood samples were obtained from 44 newborns, including 30 exposed to GDM. Women were recruited at first trimester of pregnancy and followed until delivery. GDM was assessed after a 75-g oral glucose tolerance test at 24-28 weeks of pregnancy. DNA methylation was measured at>485,000 CpG sites (Infinium HumanMethylation450 BeadChips). Ingenuity Pathway Analysis was conducted to identify metabolic pathways epigenetically affected by GDM. Our results showed that 3,271 and 3,758 genes in placenta and cord blood, respectively, were potentially differentially methylated between samples exposed or not to GDM (p-values down to 1 × 10(-06); none reached the genome-wide significance levels), with more than 25% (n = 1,029) being common to both tissues. Mean DNA methylation differences between groups were 5.7 ± 3.2% and 3.4 ± 1.9% for placenta and cord blood, respectively. These genes were likely involved in the metabolic diseases pathway (up to 115 genes (11%), p-values for pathways = 1.9 × 10(-13)diabetes mellitus p = 4.3 × 10(-11)). Among the differentially methylated genes, 326 in placenta and 117 in cord blood were also associated with newborn weight. Our results therefore suggest that GDM has epigenetic effects on genes preferentially involved in the metabolic diseases pathway, with consequences on fetal growth and development, and provide supportive evidence that DNA methylation is involved in fetal metabolic programming. PMID:23975224

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

    Science.gov (United States)

    Kubota, Takeo; Mochizuki, Kazuki

    2016-01-01

    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. PMID:27187441

  14. Epigenetic Effect of Environmental Factors on Autism Spectrum Disorders

    Science.gov (United States)

    Kubota, Takeo; Mochizuki, Kazuki

    2016-01-01

    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. PMID:27187441

  15. Epigenetic Profiling of H3K4Me3 Reveals Herbal Medicine Jinfukang-Induced Epigenetic Alteration Is Involved in Anti-Lung Cancer Activity.

    Science.gov (United States)

    Lu, Jun; Zhang, Xiaoli; Shen, Tingting; Ma, Chao; Wu, Jun; Kong, Hualei; Tian, Jing; Shao, Zhifeng; Zhao, Xiaodong; Xu, Ling

    2016-01-01

    Traditional Chinese medicine Jinfukang (JFK) has been clinically used for treating lung cancer. To examine whether epigenetic modifications are involved in its anticancer activity, we performed a global profiling analysis of H3K4Me3, an epigenomic marker associated with active gene expression, in JFK-treated lung cancer cells. We identified 11,670 genes with significantly altered status of H3K4Me3 modification following JFK treatment (P JFK. Collectively, these findings provide the first evidence that the anticancer activity of JFK involves modulation of histone modification at many cancer-related gene loci. PMID:27087825

  16. Epigenetic regulations of immediate early genes expression involved in memory formation by the amyloid precursor protein of Alzheimer disease

    OpenAIRE

    Hendrickx, Aurélie; Pierrot, Nathalie; Tasiaux, Bernadette; Schakman, Olivier; Kienlen-Campard, Pascal; De Smet, Charles; Octave, Jean-Noël

    2014-01-01

    We previously demonstrated that APP epigenetically regulates Egr1 expression both in cultured neurons and in vivo. Since Egr1 is an immediate early gene involved in memory formation, we wondered whether other early genes involved in memory were regulated by APP and we studied molecular mechanisms involved. By comparing prefrontal (PF) cortex from wild type (APP+/+) and APP knockout mice (APP-/-), we observed that APP down regulates expression of four immediate early genes, Egr1, c-Fos, Bdnf a...

  17. Epigenetic Regulations of Immediate Early Genes Expression Involved in Memory Formation by the Amyloid Precursor Protein of Alzheimer Disease

    OpenAIRE

    Hendrickx, Aurélie; Pierrot, Nathalie; Tasiaux, Bernadette; Schakman, Olivier; Kienlen-Campard, Pascal; De Smet, Charles; Octave, Jean-Noël

    2014-01-01

    We previously demonstrated that APP epigenetically regulates Egr1 expression both in cultured neurons and in vivo. Since Egr1 is an immediate early gene involved in memory formation, we wondered whether other early genes involved in memory were regulated by APP and we studied molecular mechanisms involved. By comparing prefrontal (PF) cortex from wild type (APP+/+) and APP knockout mice (APP−/−), we observed that APP down regulates expression of four immediate early genes, Egr1, c-Fos, Bdnf a...

  18. DksA involvement in transcription fidelity buffers stochastic epigenetic change.

    Science.gov (United States)

    Satory, Dominik; Gordon, Alasdair J E; Wang, Mengyu; Halliday, Jennifer A; Golding, Ido; Herman, Christophe

    2015-12-01

    DksA is an auxiliary transcription factor that interacts with RNA polymerase and influences gene expression. Depending on the promoter, DksA can be a positive or negative regulator of transcription initiation. Moreover, DksA has a substantial effect on transcription elongation where it prevents the collision of transcription and replication machineries, plays a key role in maintaining transcription elongation when translation and transcription are uncoupled and has been shown to be involved in transcription fidelity. Here, we assessed the role of DksA in transcription fidelity by monitoring stochastic epigenetic switching in the lac operon (with and without an error-prone transcription slippage sequence), partial phenotypic suppression of a lacZ nonsense allele, as well as monitoring the number of lacI mRNA transcripts produced in the presence and absence of DksA via an operon fusion and single molecule fluorescent in situ hybridization studies. We present data showing that DksA acts to maintain transcription fidelity in vivo and the role of DksA seems to be distinct from that of the GreA and GreB transcription fidelity factors. PMID:26304546

  19. An ENU mutagenesis screen identifies novel and known genes involved in epigenetic processes in the mouse

    Czech Academy of Sciences Publication Activity Database

    Daxinger, L.; Harten, S.K.; Oey, H.; Epp, Trevor; Isbel, L.; Huang, E.; Whitelaw, N.; Apedaile, A.; Sorolla, A.; Yong, J.; Bharti, V.; Sutton, J.; Ashe, A.; Pang, Z.Y.; Wallace, N.; Gerhardt, D.J.; Blewitt, M.E.; Jeddeloh, J.A.; Whitelaw, E.

    2013-01-01

    Roč. 14, č. 9 (2013). ISSN 1465-6906 Institutional support: RVO:68378050 Keywords : epigenetics * variegation * forward genetics Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 10.465, year: 2013

  20. Transcriptional, epigenetic and retroviral signatures identify regulatory regions involved in hematopoietic lineage commitment

    OpenAIRE

    Romano, Oriana; Peano, Clelia; Tagliazucchi, Guidantonio Malagoli; Petiti, Luca; Poletti, Valentina; Cocchiarella, Fabienne; Rizzi, Ermanno; Severgnini, Marco; Cavazza, Alessia; Rossi, Claudia; Pagliaro, Pasqualepaolo; Ambrosi, Alessandro; Ferrari, Giuliana; Bicciato, Silvio; De Bellis, Gianluca

    2016-01-01

    Genome-wide approaches allow investigating the molecular circuitry wiring the genetic and epigenetic programs of human somatic stem cells. Hematopoietic stem/progenitor cells (HSPC) give rise to the different blood cell types; however, the molecular basis of human hematopoietic lineage commitment is poorly characterized. Here, we define the transcriptional and epigenetic profile of human HSPC and early myeloid and erythroid progenitors by a combination of Cap Analysis of Gene Expression (CAGE...

  1. [Stress reactivity and stress-resilience in the pathogenesis of depressive disorders: involvement of epigenetic mechanisms].

    Science.gov (United States)

    Grigoryan, G A; Gulyaeva, N V

    2015-01-01

    The data of epigenetic studies of stress reactivity and resilience in the pathogenesis of depression in experimental animals and humans subjected to stress at different periods of life are analyzed. Specific chromatin modifications, first of all histone acetylation and methylation, are controlling expression of definite genes in distinct brain structures. Epigenetic modulation of particular genes related to development of pro-depressive or antidepressive stress response are discussed (5HT transporter and receptors, corticotropin releasing hormone, glucocorticoid and their receptors, BDNF and other neurotrophic factors). PMID:25966571

  2. Epigenetic Profiling of H3K4Me3 Reveals Herbal Medicine Jinfukang-Induced Epigenetic Alteration Is Involved in Anti-Lung Cancer Activity

    Directory of Open Access Journals (Sweden)

    Jun Lu

    2016-01-01

    Full Text Available Traditional Chinese medicine Jinfukang (JFK has been clinically used for treating lung cancer. To examine whether epigenetic modifications are involved in its anticancer activity, we performed a global profiling analysis of H3K4Me3, an epigenomic marker associated with active gene expression, in JFK-treated lung cancer cells. We identified 11,670 genes with significantly altered status of H3K4Me3 modification following JFK treatment (P<0.05. Gene Ontology analysis indicates that these genes are involved in tumor-related pathways, including pathway in cancer, basal cell carcinoma, apoptosis, induction of programmed cell death, regulation of transcription (DNA-templated, intracellular signal transduction, and regulation of peptidase activity. In particular, we found that the levels of H3K4Me3 at the promoters of SUSD2, CCND2, BCL2A1, and TMEM158 are significantly altered in A549, NCI-H1975, NCI-H1650, and NCI-H2228 cells, when treated with JFK. Collectively, these findings provide the first evidence that the anticancer activity of JFK involves modulation of histone modification at many cancer-related gene loci.

  3. Putative Epigenetic Involvement of the Endocannabinoid System in Anxiety- and Depression-Related Behaviors Caused by Nicotine as a Stressor.

    Science.gov (United States)

    Hayase, Tamaki

    2016-01-01

    Like various stressors, the addictive use of nicotine (NC) is associated with emotional symptoms such as anxiety and depression, although the underlying mechanisms have not yet been fully elucidated due to the complicated involvement of target neurotransmitter systems. In the elicitation of these emotional symptoms, the fundamental involvement of epigenetic mechanisms such as histone acetylation has recently been suggested. Furthermore, among the interacting neurotransmitter systems implicated in the effects of NC and stressors, the endocannabinoid (ECB) system is considered to contribute indispensably to anxiety and depression. In the present study, the epigenetic involvement of histone acetylation induced by histone deacetylase (HDAC) inhibitors was investigated in anxiety- and depression-related behavioral alterations caused by NC and/or immobilization stress (IM). Moreover, based on the contributing roles of the ECB system, the interacting influence of ECB ligands on the effects of HDAC inhibitors was evaluated in order to examine epigenetic therapeutic interventions. Anxiety-like (elevated plus-maze test) and depression-like (forced swimming test) behaviors, which were observed in mice treated with repeated (4 days) NC (subcutaneous 0.8 mg/kg) and/or IM (10 min), were blocked by the HDAC inhibitors sodium butyrate (SB) and valproic acid (VA). The cannabinoid type 1 (CB1) agonist ACPA (arachidonylcyclopropylamide; AC) also antagonized these behaviors. Conversely, the CB1 antagonist SR 141716A (SR), which counteracted the effects of AC, attenuated the anxiolytic-like effects of the HDAC inhibitors commonly in the NC and/or IM groups. SR also attenuated the antidepressant-like effects of the HDAC inhibitors, most notably in the IM group. From these results, the combined involvement of histone acetylation and ECB system was shown in anxiety- and depression-related behaviors. In the NC treatment groups, the limited influence of SR against the HDAC inhibitor

  4. Putative Epigenetic Involvement of the Endocannabinoid System in Anxiety- and Depression-Related Behaviors Caused by Nicotine as a Stressor

    Science.gov (United States)

    Hayase, Tamaki

    2016-01-01

    Like various stressors, the addictive use of nicotine (NC) is associated with emotional symptoms such as anxiety and depression, although the underlying mechanisms have not yet been fully elucidated due to the complicated involvement of target neurotransmitter systems. In the elicitation of these emotional symptoms, the fundamental involvement of epigenetic mechanisms such as histone acetylation has recently been suggested. Furthermore, among the interacting neurotransmitter systems implicated in the effects of NC and stressors, the endocannabinoid (ECB) system is considered to contribute indispensably to anxiety and depression. In the present study, the epigenetic involvement of histone acetylation induced by histone deacetylase (HDAC) inhibitors was investigated in anxiety- and depression-related behavioral alterations caused by NC and/or immobilization stress (IM). Moreover, based on the contributing roles of the ECB system, the interacting influence of ECB ligands on the effects of HDAC inhibitors was evaluated in order to examine epigenetic therapeutic interventions. Anxiety-like (elevated plus-maze test) and depression-like (forced swimming test) behaviors, which were observed in mice treated with repeated (4 days) NC (subcutaneous 0.8 mg/kg) and/or IM (10 min), were blocked by the HDAC inhibitors sodium butyrate (SB) and valproic acid (VA). The cannabinoid type 1 (CB1) agonist ACPA (arachidonylcyclopropylamide; AC) also antagonized these behaviors. Conversely, the CB1 antagonist SR 141716A (SR), which counteracted the effects of AC, attenuated the anxiolytic-like effects of the HDAC inhibitors commonly in the NC and/or IM groups. SR also attenuated the antidepressant-like effects of the HDAC inhibitors, most notably in the IM group. From these results, the combined involvement of histone acetylation and ECB system was shown in anxiety- and depression-related behaviors. In the NC treatment groups, the limited influence of SR against the HDAC inhibitor

  5. Epigenetic responses to heat stress at different time scales and the involvement of small RNAs

    OpenAIRE

    Stief, Anna; Brzezinka, Krzysztof; Lämke, Jörn; Bäurle, Isabel

    2014-01-01

    The hypothesis that plants can benefit from a memory of past stress exposure has recently attracted a lot of attention. Here, we discuss two different examples of heat stress memory to elucidate the potential benefits that epigenetic responses may provide at both the level of acclimation of the individual plant and adaptation at a species-wide level. Specifically, we discuss how microRNAs regulate the heat stress memory and thereby increase survival upon a recurring heat stress. Secondly, we ...

  6. Involvement of Epigenetic Mechanisms in the Regulation of Secreted Phospholipase A2 Expressions in Jurkat Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Mario Menschikowski

    2008-11-01

    Full Text Available Epigenetic changes provide a frequent mechanism for transcriptional silencing of genes in cancer cells. We previously established that epigenetic mechanisms are important for control of group IIA phospholipase A2 (PLA2G2A gene transcription in human DU-145 prostate cells. In this study, we analyzed the involvement of such mechanisms in the regulation of five sPLA2 isozymes and the M-type receptor of sPLA2 (sPLA2-R in human leukemic Jurkat cells. These cells constitutively expressed sPLA2-IB, sPLA2-III, sPLA2-X, and sPLA2-R but not sPLA2-IIA and sPLA2-V. Transcription of sPLA2-IIA and sPLA2-V was, however, detected after exposure of cells to the DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC. Expression of sPLA2-IIA was further enhanced by additional exposure to interferon-γ and blocked by inhibitors of specificity protein 1, nuclear factor κB, and Janus kinase/signal transducer and activator of transcription-dependent pathways. Sequence analysis and methylation-specific polymerase chain reaction of bisulfite-modified genomic DNA revealed two 5′-CpG sites (-111 and -82 in the sPLA2-IIA proximal promoter that were demethylated after 5-aza-dC treatment. These sites may be involved in the DNA binding of specificity protein 1 and other transcription factors. Similar findings after treatment of human U937 leukemia cells with 5-aza-dC indicate that this mechanism of PLA2G2A gene silencing is not restricted to Jurkat and DU-145 cells. These data establish that regulation of sPLA2-IIA and sPLA2-V in Jurkat and other cells involves epigenetic silencing by DNA hypermethylation.

  7. Putative Epigenetic Involvement of the Endocannabinoid System in Anxiety- and Depression-Related Behaviors Caused by Nicotine as a Stressor.

    Directory of Open Access Journals (Sweden)

    Tamaki Hayase

    Full Text Available Like various stressors, the addictive use of nicotine (NC is associated with emotional symptoms such as anxiety and depression, although the underlying mechanisms have not yet been fully elucidated due to the complicated involvement of target neurotransmitter systems. In the elicitation of these emotional symptoms, the fundamental involvement of epigenetic mechanisms such as histone acetylation has recently been suggested. Furthermore, among the interacting neurotransmitter systems implicated in the effects of NC and stressors, the endocannabinoid (ECB system is considered to contribute indispensably to anxiety and depression. In the present study, the epigenetic involvement of histone acetylation induced by histone deacetylase (HDAC inhibitors was investigated in anxiety- and depression-related behavioral alterations caused by NC and/or immobilization stress (IM. Moreover, based on the contributing roles of the ECB system, the interacting influence of ECB ligands on the effects of HDAC inhibitors was evaluated in order to examine epigenetic therapeutic interventions. Anxiety-like (elevated plus-maze test and depression-like (forced swimming test behaviors, which were observed in mice treated with repeated (4 days NC (subcutaneous 0.8 mg/kg and/or IM (10 min, were blocked by the HDAC inhibitors sodium butyrate (SB and valproic acid (VA. The cannabinoid type 1 (CB1 agonist ACPA (arachidonylcyclopropylamide; AC also antagonized these behaviors. Conversely, the CB1 antagonist SR 141716A (SR, which counteracted the effects of AC, attenuated the anxiolytic-like effects of the HDAC inhibitors commonly in the NC and/or IM groups. SR also attenuated the antidepressant-like effects of the HDAC inhibitors, most notably in the IM group. From these results, the combined involvement of histone acetylation and ECB system was shown in anxiety- and depression-related behaviors. In the NC treatment groups, the limited influence of SR against the HDAC inhibitor

  8. Chemical Epigenetics Alters the Secondary Metabolite Composition of Guttate Excreted by an Atlantic-Forest-Soil-Derived Penicillium citreonigrum

    OpenAIRE

    Wang, Xiaoru; Filho, José G. Sena; Hoover, Ashley R.; King, Jarrod B.; Ellis, Trevor K.; Powell, Douglas R.; Cichewicz, Robert H.

    2010-01-01

    Chemical epigenetic manipulation of Penicillium citreonigrum led to profound changes in the secondary metabolite profile of its guttate. While guttate from control cultures exhibited a relatively simple assemblage of secondary metabolites, the guttate collected from cultures treated with 50 μM 5-azacytidine (a DNA methyltransferase inhibitor) were highly enriched in compounds representing at least three distinct biosynthetic families. The metabolites obtained from the fungus included six azap...

  9. GM1 Ganglioside is Involved in Epigenetic Activation Loci of Neuronal Cells.

    Science.gov (United States)

    Tsai, Yi-Tzang; Itokazu, Yutaka; Yu, Robert K

    2016-02-01

    Gangliosides are sialic acid-containing glycosphingolipids that are most abundant in the nerve tissues. The quantity and expression pattern of gangliosides in brain change drastically throughout development and are mainly regulated through stage-specific expression of glycosyltransferase (ganglioside synthase) genes. We previously demonstrated that acetylation of histones H3 and H4 on the N-acetylgalactosaminyltransferase I (GalNAcT, GA2/GM2/GD2/GT2-synthase) gene promoter resulted in recruitment of trans-activation factors. In addition, we reported that epigenetic activation of the GalNAcT gene was also detected as accompanied by an apparent induction of neuronal differentiation in neural stem cells responding to an exogenous supplement of ganglioside GM1. Here, we present evidence supporting the concept that nuclear GM1 is associated with gene regulation in neuronal cells. We found that nuclear GM1 binds acetylated histones on the promoters of the GalNAcT and NeuroD1 genes in differentiated neurons. Our study demonstrates for the first time that GM1 interacts with chromatin via acetylated histones at the nuclear periphery of neuronal cells. PMID:26498762

  10. The Role of Epigenetics in the Latent Effects of Early Life Exposure to Obesogenic Endocrine Disrupting Chemicals.

    Science.gov (United States)

    Stel, Jente; Legler, Juliette

    2015-10-01

    Recent research supports a role for exposure to endocrine-disrupting chemicals (EDCs) in the global obesity epidemic. Obesogenic EDCs have the potential to inappropriately stimulate adipogenesis and fat storage, influence metabolism and energy balance and increase susceptibility to obesity. Developmental exposure to obesogenic EDCs is proposed to interfere with epigenetic programming of gene regulation, partly by activation of nuclear receptors, thereby influencing the risk of obesity later in life. The goal of this minireview is to briefly describe the epigenetic mechanisms underlying developmental plasticity and to evaluate the evidence of a mechanistic link between altered epigenetic gene regulation by early life EDC exposure and latent onset of obesity. We summarize the results of recent in vitro, in vivo, and transgenerational studies, which clearly show that the obesogenic effects of EDCs such as tributyltin, brominated diphenyl ether 47, and polycyclic aromatic hydrocarbons are mediated by the activation and associated altered methylation of peroxisome proliferator-activated receptor-γ, the master regulator of adipogenesis, or its target genes. Importantly, studies are emerging that assess the effects of EDCs on the interplay between DNA methylation and histone modifications in altered chromatin structure. These types of studies coupled with genome-wide rather than gene-specific analyses are needed to improve mechanistic understanding of epigenetic changes by EDC exposure. Current advances in the field of epigenomics have led to the first potential epigenetic markers for obesity that can be detected at birth, providing an important basis to determine the effects of developmental exposure to obesogenic EDCs in humans. PMID:26241072

  11. DUBbing Cancer: Deubiquitylating Enzymes Involved in Epigenetics, DNA Damage and the Cell Cycle As Therapeutic Targets

    Science.gov (United States)

    Pinto-Fernandez, Adan; Kessler, Benedikt M.

    2016-01-01

    Controlling cell proliferation is one of the hallmarks of cancer. A number of critical checkpoints ascertain progression through the different stages of the cell cycle, which can be aborted when perturbed, for instance by errors in DNA replication and repair. These molecular checkpoints are regulated by a number of proteins that need to be present at the right time and quantity. The ubiquitin system has emerged as a central player controlling the fate and function of such molecules such as cyclins, oncogenes and components of the DNA repair machinery. In particular, proteases that cleave ubiquitin chains, referred to as deubiquitylating enzymes (DUBs), have attracted recent attention due to their accessibility to modulation by small molecules. In this review, we describe recent evidence of the critical role of DUBs in aspects of cell cycle checkpoint control, associated DNA repair mechanisms and regulation of transcription, representing pathways altered in cancer. Therefore, DUBs involved in these processes emerge as potentially critical targets for the treatment of not only hematological, but potentially also solid tumors.

  12. Differential expression of genes involved in the epigenetic regulation of cell identity in normal human mammary cell commitment and differentiation

    Directory of Open Access Journals (Sweden)

    Danila Coradini

    2014-10-01

    Full Text Available The establishment and maintenance of mammary epithelial cell identity depends on the activity of a group of proteins, collectively called maintenance proteins, that act as epigenetic regulators of gene transcription through DNA methylation, histone modification, and chromatin remodeling. Increasing evidence indicates that dysregulation of these crucial proteins may disrupt epithelial cell integrity and trigger breast tumor initiation. Therefore, we explored in silico the expression pattern of a panel of 369 genes known to be involved in the establishment and maintenance of epithelial cell identity and mammary gland remodeling in cell subpopulations isolated from normal human mammary tissue and selectively enriched in their content of bipotent progenitors, committed luminal progenitors, and differentiated myoepithelial or differentiated luminal cells. The results indicated that, compared to bipotent cells, differentiated myoepithelial and luminal subpopulations were both characterized by the differential expression of 4 genes involved in cell identity maintenance: CBX6 and PCGF2, encoding proteins belonging to the Polycomb group, and SMARCD3 and SMARCE1, encoding proteins belonging to the Trithorax group. In addition to these common genes, the myoepithelial phenotype was associated with the differential expression of HDAC1, which encodes histone deacetylase 1, whereas the luminal phenotype was associated with the differential expression of SMARCA4 and HAT1, which encode a Trithorax protein and histone acetylase 1, respectively. The luminal compartment was further characterized by the overexpression of ALDH1A3 and GATA3, and the down-regulation of NOTCH4 and CCNB1, with the latter suggesting a block in cell cycle progression at the G2 phase. In contrast, myoepithelial differentiation was associated with the overexpression of MYC and the down-regulation of CCNE1, with the latter suggesting a block in cell cycle progression at the G1 phase.

  13. Maintenance of Epigenetic Information.

    Science.gov (United States)

    Almouzni, Geneviève; Cedar, Howard

    2016-01-01

    SUMMARYThe genome is subject to a diverse array of epigenetic modifications from DNA methylation to histone posttranslational changes. Many of these marks are somatically stable through cell division. This article focuses on our knowledge of the mechanisms governing the inheritance of epigenetic marks, particularly, repressive ones, when the DNA and chromatin template are duplicated in S phase. This involves the action of histone chaperones, nucleosome-remodeling enzymes, histone and DNA methylation binding proteins, and chromatin-modifying enzymes. Last, the timing of DNA replication is discussed, including the question of whether this constitutes an epigenetic mark that facilitates the propagation of epigenetic marks. PMID:27141050

  14. Chemical basis for the recognition of trimethyllysine by epigenetic reader proteins

    Science.gov (United States)

    Kamps, Jos J. A. G.; Huang, Jiaxin; Poater, Jordi; Xu, Chao; Pieters, Bas J. G. E.; Dong, Aiping; Min, Jinrong; Sherman, Woody; Beuming, Thijs; Matthias Bickelhaupt, F.; Li, Haitao; Mecinović, Jasmin

    2015-11-01

    A large number of structurally diverse epigenetic reader proteins specifically recognize methylated lysine residues on histone proteins. Here we describe comparative thermodynamic, structural and computational studies on recognition of the positively charged natural trimethyllysine and its neutral analogues by reader proteins. This work provides experimental and theoretical evidence that reader proteins predominantly recognize trimethyllysine via a combination of favourable cation-π interactions and the release of the high-energy water molecules that occupy the aromatic cage of reader proteins on the association with the trimethyllysine side chain. These results have implications in rational drug design by specifically targeting the aromatic cage of readers of trimethyllysine.

  15. Epigenetic and genetic factors in the cellular response to radiations and DNA-damaging chemicals

    International Nuclear Information System (INIS)

    DNA-damaging agents are widely used as therapeutic tools for a variety of disease states. Many such agents are considered to produce detrimental side effects. Thus, it is important to evaluate both therapeutic efficacy and potential risk. DNA-damaging agents can be so evaluated by comparison to agents whose therapeutic benefit and potential hazards are better known. We propose a framework for such comparison, demonstrating that a simple transformation of cytotoxicity-dose response patterns permits a facile comparison of variation between cells exposed to a single DNA-damaging agent or to different cytotoxic agents. Further, by transforming data from experiments which compare responses of 2 cell populations to an effects ratio, different patterns for the changes in cytotoxicity produced by epigenetic and genetic factors were compared. Using these transformations, we found that there is a wide variation (a factor of 4) between laboratories for a single agent (UVC) and only a slightly larger variation (factor of 6) between normal cell response for different types of DNA-damaging agents (x-ray, UVC, alkylating agents, crosslinking agents). Epigenetic factors such as repair and recovery appear to be a factor only at higher dose levels. Comparison in the cytotoxic effect of a spectrum of DNA-damaging agents in xeroderma pigmentosum, ataxia telangiectasia, and Fanconi's anemia cells indicates significantly different patterns, implying that the effect, and perhaps the nature, of these genetic conditions are quite different

  16. Epigenetics and aging

    Science.gov (United States)

    Pal, Sangita; Tyler, Jessica K.

    2016-01-01

    Over the past decade, a growing number of studies have revealed that progressive changes to epigenetic information accompany aging in both dividing and nondividing cells. Functional studies in model organisms and humans indicate that epigenetic changes have a huge influence on the aging process. These epigenetic changes occur at various levels, including reduced bulk levels of the core histones, altered patterns of histone posttranslational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression, during both organismal aging and replicative senescence. The end result of epigenetic changes during aging is altered local accessibility to the genetic material, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability. Strikingly, certain types of epigenetic information can function in a transgenerational manner to influence the life span of the offspring. Several important conclusions emerge from these studies: rather than being genetically predetermined, our life span is largely epigenetically determined; diet and other environmental influences can influence our life span by changing the epigenetic information; and inhibitors of epigenetic enzymes can influence life span of model organisms. These new findings provide better understanding of the mechanisms involved in aging. Given the reversible nature of epigenetic information, these studies highlight exciting avenues for therapeutic intervention in aging and age-associated diseases, including cancer. PMID:27482540

  17. Epigenetics in an ecotoxicological context.

    Science.gov (United States)

    Vandegehuchte, Michiel B; Janssen, Colin R

    2014-04-01

    Epigenetics can play a role in interactions between chemicals and exposed species, between species and abiotic ecosystem components or between species of the same or another population in a community. Technological progress and advanced insights into epigenetic processes have led to the description of epigenetic features (mainly DNA methylation) in many ecologically relevant species: algae, plants, several invertebrates and fish. Epigenetic changes in plants, insects and cladocerans have been reported to be induced by various environmental stress factors including nutrition or water deficiency, grazing, light or temperature alterations, social environment, and dissolved organic matter concentrations. As regards chemicals, studies in rats and mice exposed to specific pesticides, hydrocarbons, dioxins, and endocrine disrupting chemicals demonstrated the induction of epigenetic changes, suggesting the need for further research with these substances in an ecotoxicological context. In fish and plants, exposure to polyaromatic hydrocarbons, metals, and soluble fractions of solid waste affected the epigenetic status. A novel concept in ecotoxicological epigenetics is the induction of transgenerational stress resistance upon chemical exposure, as demonstrated in rice exposed to metals. Evaluating epigenetics in ecotoxicological field studies is a second relatively new approach. A cryptic lineage of earthworms had developed arsenic tolerance in the field, concurrent with specific DNA methylation patterns. Flatfish caught in the framework of environmental monitoring had developed tumours, exhibiting specific DNA methylation patterns. Two main potential implications of epigenetics in an ecotoxicological context are (1) the possibility of transgenerationally inherited, chemical stress-induced epigenetic changes with associated phenotypes and (2) epigenetically induced adaptation to stress upon long-term chemical exposure. Key knowledge gaps are concerned with the causality of

  18. The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer.

    Science.gov (United States)

    Klenova, Elena M; Morse, Herbert C; Ohlsson, Rolf; Lobanenkov, Victor V

    2002-10-01

    CTCF is a ubiquitous 11 zinc finger (ZF) protein with highly versatile functions: in addition to transcriptional silencing or activating in a context-dependent fashion, it organizes epigenetically controlled chromatin insulators that regulate imprinted genes in soma. Recently, we have identified a CTCF paralogue, termed BORIS for Brother of the Regulator of Imprinted Sites, that is expressed only in the testis. BORIS has the same exons encoding the 11 ZF domain as mammalian CTCF genes, and hence interacts with similar cis elements, but encodes amino and carboxy termini distinct from those in CTCF. Normally, CTCF and BORIS are expressed in a mutually exclusive pattern that correlates with re-setting of methylation marks during male germ cell differentiation. The antagonistic features of these two gene siblings are underscored by showing that while CTCF overexpression blocks cell proliferation, expression of BORIS in normally BORIS-negative cells promotes cell growth which can lead to transformation. The suggestion that BORIS directs epigenetic reprogramming at CTCF target sites impinges on the observations that human BORIS is not only abnormally activated in a wide range of human cancers, but also maps to the cancer-associated amplification region at 20q13. The sibling rivalry occasioned by aberrant expression of BORIS in cancer may interfere with normal functions of CTCF including growth suppression, and contribute to epigenetic dysregulation which is a common feature in human cancer. PMID:12191639

  19. EPIGENETIC MODIFICATIONS OF SWINE GENOME

    OpenAIRE

    Kristina Budimir; Gordana Kralik; Vladimir Margeta

    2013-01-01

    Epigenetics is represents a new way of genome analysis, respectively gene expression that occurs without DNA sequence change. Changes that occur are epigenetic modifications and they include post-translational histone modification and DNA methylation. Chemical groups that are added on DNA molecule cause changes in DNA and create epigenome. The consequence of that is appearance of imprinted genes in genome. Genetic imprinting is epigenetic modification in which one of inherited alleles inactiv...

  20. Epigenetic regulation of neurodevelopmental genes in response to in utero exposure to phthalate plastic chemicals: How can we delineate causal effects?

    Science.gov (United States)

    Ponsonby, Anne-Louise; Symeonides, Christos; Vuillermin, Peter; Mueller, Jochen; Sly, Peter D; Saffery, Richard

    2016-07-01

    Accumulating evidence, from animal models and human observational studies, implicates the in utero (and early postnatal) environment in the 'programming' of risk for a variety of adverse outcomes and health trajectories. The modern environment is replete with man-made compounds such as plastic product chemicals (PPC), including phenols and phthalates. Evidence from several human cohorts implicates exposure to these chemicals in adverse offspring neurodevelopment, though a direct causal relationship has not been firmly established. In this review we consider a potential causal pathway that encompasses epigenetic human variation, and how we might test this mechanistic hypothesis in human studies. In the first part of this report we outline how PPCs induce epigenetic change, focusing on the brain derived neurotrophic factor (BDNF) gene, a key regulator of neurodevelopment. Further, we discuss the role of the epigenetics of BDNF and other genes in neurodevelopment and the emerging human evidence of an association between phthalate exposure and adverse offspring neurodevelopment. We discuss aspects of epidemiological and molecular study design and analysis that could be employed to strengthen the level of human evidence to infer causality. We undertake this using an exemplar recent research example: maternal prenatal smoking, linked to methylation change at the aryl hydrocarbon receptor repressor (AHRR) gene at birth, now shown to mediate some of the effects of maternal smoking on birth weight. Characterizing the relationship between the modern environment and the human molecular pathways underpinning its impact on early development is paramount to understanding the public health significance of modern day chemical exposures. PMID:27208563

  1. Epigenetic silencing of p21 by long non-coding RNA HOTAIR is involved in the cell cycle disorder induced by cigarette smoke extract.

    Science.gov (United States)

    Liu, Yi; Wang, Bairu; Liu, Xinlu; Lu, Lu; Luo, Fei; Lu, Xiaolin; Shi, Le; Xu, Wenchao; Liu, Qizhan

    2016-01-01

    Long noncoding RNAs (lncRNAs), which are epigenetic regulators, are involved in human malignancies. Little is known, however, about the molecular mechanisms for lncRNA regulation of genes induced by cigarette smoke. We recently found that, in human bronchial epithelial (HBE) cells, the lncRNA, Hox transcript antisense intergenic RNA (HOTAIR), is associated with changes in the cell cycle caused by cigarette smoke extract (CSE). In the present study, we report that increased expression of HOTAIR and enhancer of zeste homolog 2 (EZH2), and tri-methylation of Lys 27 of histone H3 (H3K27me3), affect cell cycle progression during CSE-induced transformation of HBE cells. Inhibition of HOTAIR and EZH2 by siRNAs attenuated CSE-induced decreases of p21 levels. Further, ChIP assays verified that HOTAIR and EZH2 were needed to maintain the interaction of H3K27me3 with the promoter regions of p21; combined use of a HOTAIR plasmid and EZH2 siRNA supported this observation. Thus, HOTAIR epigenetic silencing of p21 via EZH2-mediated H3K27 trimethylation contributes to changes in the cell cycle induced by CSE. These observations provide further understanding of the regulation of CSE-induced lung carcinogenesis and identify new therapeutic targets. PMID:26506537

  2. Epigenetics in the hematologic malignancies

    OpenAIRE

    Fong, Chun Yew; Morison, Jessica; Dawson, Mark A.

    2014-01-01

    A wealth of genomic and epigenomic data has identified abnormal regulation of epigenetic processes as a prominent theme in hematologic malignancies. Recurrent somatic alterations in myeloid malignancies of key proteins involved in DNA methylation, post-translational histone modification and chromatin remodeling have highlighted the importance of epigenetic regulation of gene expression in the initiation and maintenance of various malignancies. The rational use of targeted epigenetic therapies...

  3. 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...

  4. A bioinformatics analysis of Lamin-A regulatory network: a perspective on epigenetic involvement in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Arancio, Walter

    2012-04-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare human genetic disease that leads to premature aging. HGPS is caused by mutation in the Lamin-A (LMNA) gene that leads, in affected young individuals, to the accumulation of the progerin protein, usually present only in aging differentiated cells. Bioinformatics analyses of the network of interactions of the LMNA gene and transcripts are presented. The LMNA gene network has been analyzed using the BioGRID database (http://thebiogrid.org/) and related analysis tools such as Osprey (http://biodata.mshri.on.ca/osprey/servlet/Index) and GeneMANIA ( http://genemania.org/). The network of interaction of LMNA transcripts has been further analyzed following the competing endogenous (ceRNA) hypotheses (RNA cross-talk via microRNAs [miRNAs]) and using the miRWalk database and tools (www.ma.uni-heidelberg.de/apps/zmf/mirwalk/). These analyses suggest particular relevance of epigenetic modifiers (via acetylase complexes and specifically HTATIP histone acetylase) and adenosine triphosphate (ATP)-dependent chromatin remodelers (via pBAF, BAF, and SWI/SNF complexes). PMID:22533413

  5. Epigenetic microRNA Regulation

    DEFF Research Database (Denmark)

    Wiklund, Erik Digman

    2011-01-01

    and confirming transcriptional start sites can be difficult. Epigenetics, gene regulatory and DNA modification mechanisms not involving a change to the primary sequence, have been implied in the regulation of a number of miRNA loci. Both epigenetic and miRNA signatures are broadly altered in cancer......, and are thought to play essential roles in cancer etiology and progression. Here, we aimed to identify epigenetic miRNA deregulation in bladder and oral carcinoma, and to develop a robust approach to epigenetic miRNA prediction and detection. In addition, non-canonical epigenetic functions directed by a nuclear...... miRNA were investigated. In summary, we report that the miR-200 family and miR-205 are coordinately epigenetically regulated in a variety of cell lines, tumors and normal tissues. MiR-200c expression is correlated with bladder cancer disease progression, and miR-375 levels in oral rinse can...

  6. 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.

  7. The Mendelian disorders of the epigenetic machinery

    OpenAIRE

    Bjornsson, Hans Tomas

    2015-01-01

    The Mendelian disorders of the epigenetic machinery are genetic disorders that involve disruption of the various components of the epigenetic machinery (writers, erasers, readers, and remodelers) and are thus expected to have widespread downstream epigenetic consequences. Studying this group may offer a unique opportunity to learn about the role of epigenetics in health and disease. Among these patients, neurological dysfunction and, in particular, intellectual disability appears to be a comm...

  8. The physics of epigenetics

    CERN Document Server

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

    2015-01-01

    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 multi-scale physical mechanisms that govern the biological processes behind the initiation, spreading and inheritance of epigenetic states. These include not only the change in the molecular properties associated with the chemical modifications of DNA and histone proteins - such as methylation and acetylation - but also less conventional ones, such as 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 m...

  9. The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory.

    Science.gov (United States)

    Yoshida, Keisuke; Maekawa, Toshio; Zhu, Yujuan; Renard-Guillet, Claire; Chatton, Bruno; Inoue, Kentaro; Uchiyama, Takeru; Ishibashi, Ken-ichi; Yamada, Takuji; Ohno, Naohito; Shirahige, Katsuhiko; Okada-Hatakeyama, Mariko; Ishii, Shunsuke

    2015-10-01

    Immunological memory is thought to be mediated exclusively by lymphocytes. However, enhanced innate immune responses caused by a previous infection increase protection against reinfection, which suggests the presence of innate immunological memory. Here we identified an important role for the stress-response transcription factor ATF7 in innate immunological memory. ATF7 suppressed a group of genes encoding factors involved in innate immunity in macrophages by recruiting the histone H3K9 dimethyltransferase G9a. Treatment with lipopolysaccharide, which mimics bacterial infection, induced phosphorylation of ATF7 via the kinase p38, which led to the release of ATF7 from chromatin and a decrease in repressive histone H3K9me2 marks. A partially disrupted chromatin structure and increased basal expression of target genes were maintained for long periods, which enhanced resistance to pathogens. ATF7 might therefore be important in controlling memory in cells of the innate immune system. PMID:26322480

  10. Epigenetic mechanisms involved in differential MDR1 mRNA expression between gastric and colon cancer cell lines and rationales for clinical chemotherapy

    Directory of Open Access Journals (Sweden)

    Kim Kyung-Jong

    2008-08-01

    Full Text Available Abstract Background The membrane transporters such as P-glycoprotein (Pgp, the MDR1 gene product, are one of causes of treatment failure in cancer patients. In this study, the epigenetic mechanisms involved in differential MDR1 mRNA expression were compared between 10 gastric and 9 colon cancer cell lines. Methods The MDR1 mRNA levels were determined using PCR and real-time PCR assays after reverse transcription. Cytotoxicity was performed using the MTT assay. Methylation status was explored by quantification PCR-based methylation and bisulfite DNA sequencing analyses. Results The MDR1 mRNA levels obtained by 35 cycles of RT-PCR in gastric cancer cells were just comparable to those obtained by 22 cycles of RT-PCR in colon cancer cells. Real-time RT-PCR analysis revealed that MDR1 mRNA was not detected in the 10 gastric cancer cell lines but variable MDR1 mRNA levels in 7 of 9 colon cancer cell lines except the SNU-C5 and HT-29 cells. MTT assay showed that Pgp inhibitors such as cyclosporine A, verapamil and PSC833 sensitized Colo320HSR (colon, highest MDR1 expression but not SNU-668 (gastric, highest and SNU-C5 (gastric, no expression to paclitaxel. Quantification PCR-based methylation analysis revealed that 90% of gastric cancer cells, and 33% of colon cancer cells were methylated, which were completely matched with the results obtained by bisulfite DNA sequencing analysis. 5-aza-2'-deoxcytidine (5AC, a DNA methyltransferase inhibitor increased the MDR1 mRNA levels in 60% of gastric cells, and in 11% of colon cancer cells. Trichostatin A (TSA, histone deacetylase inhibitor increased the MDR1 mRNA levels in 70% of gastric cancer cells and 55% of colon cancer cells. The combined treatment of 5AC with TSA increased the MDR1 mRNA levels additively in 20% of gastric cancer cells, but synergistically in 40% of gastric and 11% of colon cancer cells. Conclusion These results indicate that the MDR1 mRNA levels in gastric cancer cells are significantly

  11. Epigenetics and nutritional environmental signals.

    Science.gov (United States)

    Mazzio, Elizabeth A; Soliman, Karam F A

    2014-07-01

    All terrestrial life is influenced by multi-directional flows of information about its environment, enabling malleable phenotypic change through signals, chemical processes, or various forms of energy that facilitate acclimatization. Billions of biological co-inhabitants of the earth, including all plants and animals, collectively make up a genetic/epigenetic ecosystem by which adaptation/survival (inputs and outputs) are highly interdependent on one another. As an ecosystem, the solar system, rotation of the planets, changes in sunlight, and gravitational pull influence cyclic epigenetic transitions and chromatin remodeling that constitute biological circadian rhythms controlling senescence. In humans, adverse environmental conditions such as poverty, stress, alcohol, malnutrition, exposure to pollutants generated from industrialization, man-made chemicals, and use of synthetic drugs can lead to maladaptive epigenetic-related illnesses with disease-specific genes being atypically activated or silenced. Nutrition and dietary practices are one of the largest facets in epigenetic-related metabolism, where specific "epi-nutrients" can stabilize the genome, given established roles in DNA methylation, histone modification, and chromatin remodeling. Moreover, food-based "epi-bioactive" constituents may reverse maladaptive epigenetic patterns, not only prior to conception and during fetal/early postnatal development but also through adulthood. In summary, in contrast to a static genomic DNA structure, epigenetic changes are potentially reversible, raising the hope for therapeutic and/or dietary interventions that can reverse deleterious epigenetic programing as a means to prevent or treat major illnesses. PMID:24861811

  12. EPIGENETIC MODIFICATIONS OF SWINE GENOME

    Directory of Open Access Journals (Sweden)

    Kristina Budimir

    2013-06-01

    Full Text Available Epigenetics is represents a new way of genome analysis, respectively gene expression that occurs without DNA sequence change. Changes that occur are epigenetic modifications and they include post-translational histone modification and DNA methylation. Chemical groups that are added on DNA molecule cause changes in DNA and create epigenome. The consequence of that is appearance of imprinted genes in genome. Genetic imprinting is epigenetic modification in which one of inherited alleles inactivates. Its influence can be seen on productive and reproductive traits. Discovering new imprinted genes is important because of their conservation and understanding their function.

  13. Epigenetic Suppression of GADs Expression is Involved in Temporal Lobe Epilepsy and Pilocarpine-Induced Mice Epilepsy.

    Science.gov (United States)

    Wang, Jin-Gang; Cai, Qing; Zheng, Jun; Dong, Yu-Shu; Li, Jin-Jiang; Li, Jing-Chen; Hao, Guang-Zhi; Wang, Chao; Wang, Ju-Lei

    2016-07-01

    Recent studies have shown that histone acetylation is involved with the regulation of enzyme glutamate decarboxylases (GADs), including GAD67 and GAD65. Here, we investigated the histone acetylation modifications of GADs in the pathogenesis of epilepsy and explored the therapeutic effect of a novel second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585 in epilepsy animals. We revealed the suppression of GADs protein and mRNA level, and histone hypoacetylation in patients with temporal lobe epilepsy and pilocarpine-induced epilepsy mice model. Double-immunofluorescence also indicated that the hypoacetyl-H3 was located in hippocampal GAD67/GAD65 positive neurons in epilepsy mice. JNJ-26481585 significantly reversed the decrease of the GAD67/GAD65 both protein and mRNA levels, and the histone hypoacetylation of GABAergic neurons in epilepsy mice. Meanwhile, single-cell real-time PCR performed in GFP-GAD67/GAD65 transgenic mice demonstrated that JNJ-26481585 induced increase of GAD67/GAD65 mRNA level in GABAergic neurons. Furthermore, JNJ-26481585 significantly alleviated the epileptic seizures in mice model. Together, our findings demonstrate inhibition of GADs gene via histone acetylation plays an important role in the pathgenesis of epilepsy, and suggest JNJ-26481585 as a promising therapeutic strategy for epilepsy. PMID:27220336

  14. Epigenetic Treatments for Cognitive Impairments

    OpenAIRE

    Day, Jeremy J.; Sweatt, J. David

    2011-01-01

    Epigenetic mechanisms integrate signals from diverse intracellular transduction cascades and in turn regulate genetic readout. Accumulating evidence has revealed that these mechanisms are critical components of ongoing physiology and function in the adult nervous system, and are essential for many cognitive processes, including learning and memory. Moreover, a number of psychiatric disorders and syndromes that involve cognitive impairments are associated with altered epigenetic function. In t...

  15. Miscible viscous fingering involving production of gel by chemical reactions

    Science.gov (United States)

    Nagatsu, Yuichiro; Hoshino, Kenichi

    2015-11-01

    We have experimentally investigated miscible viscous fingering with chemical reactions producing gel. Here, two systems were employed. In one system, sodium polyacrylate (SPA) solution and aluminum ion (Al3 +) solution were used as the more and less viscous liquids, respectively. In another system, SPA solution and ferric ion (Fe3 +) solution were used as the more and less viscous liquids, respectively. In the case of Al3 +, displacement efficiency was smaller than that in the non-reactive case, whereas in the case of Fe3 +, the displacement efficiency was larger. We consider that the difference in change of the patterns in the two systems will be caused by the difference in the properties of the gels. Therefore, we have measured the rheological properties of the gels by means of a rheometer. We discuss relationship between the VF patterns and the rheological measurement.

  16. Complex disease, gender and epigenetics.

    Science.gov (United States)

    Kaminsky, Zachary; Wang, Sun-Chong; Petronis, Arturas

    2006-01-01

    Gender differences in susceptibility to complex disease such as asthma, diabetes, lupus, autism and major depression, among numerous other disorders, represent one of the hallmarks of non-Mendelian biology. It has been generally accepted that endocrinological differences are involved in the sexual dimorphism of complex disease; however, specific molecular mechanisms of such hormonal effects have not been elucidated yet. This paper will review evidence that sex hormone action may be mediated via gene-specific epigenetic modifications of DNA and histones. The epigenetic modifications can explain sex effects at DNA sequence polymorphisms and haplotypes identified in gender-stratified genetic linkage and association studies. Hormone-induced DNA methylation and histone modification changes at specific gene regulatory regions may increase or reduce the risk of a disease. The epigenetic interpretation of sexual dimorphism fits well into the epigenetic theory of complex disease, which argues for the primary pathogenic role of inherited and/or acquired epigenetic misregulation rather than DNA sequence variation. The new experimental strategies, especially the high throughput microarray-based epigenetic profiling, can be used for testing the epigenetic hypothesis of gender effects in complex diseases. PMID:17438668

  17. Epigenetic regulatory mechanisms associated with infertility

    DEFF Research Database (Denmark)

    Minocherhomji, Sheroy; Madon, Prochi F; Parikh, Firuza R

    2010-01-01

    Infertility is a complex human condition and is known to be caused by numerous factors including genetic alterations and abnormalities. Increasing evidence from studies has associated perturbed epigenetic mechanisms with spermatogenesis and infertility. However, there has been no consensus...... on whether one or a collective of these altered states is responsible for the onset of infertility. Epigenetic alterations involve changes in factors that regulate gene expression without altering the physical sequence of DNA. Understanding these altered epigenetic states at the genomic level along...... with the phenotype could further determine what possible mechanisms are involved. This paper reviews certain mechanisms of epigenetic regulation with particular emphasis on their possible role in infertility....

  18. Epigenetics protocols

    Directory of Open Access Journals (Sweden)

    Manuela Monti

    2012-06-01

    Full Text Available Thanks to the creative effort of Prof. Trygve O. Tollefsbol (Dept. of Biology, University of Alabama at Birmingham, USA we can handle the second edition in just seven years of this must needed volume devoted to the study of the epigenome. In the very same window-time the field of epigenetics is dramatically changed as for the technical tools employed by the pupils of this pervasive discipline: actually there is no one hot topics in biology (e.g., development, differentiation, genomic toxicity and medicine .....

  19. Epigenetic Memory in Mammals

    OpenAIRE

    Migicovsky, Zoë; Kovalchuk, Igor

    2011-01-01

    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 ...

  20. Paleontological, mineralogical and chemical studies of syngenetic and epigenetic Pb-Zn-Ba-P mineralizations at the stratotype of the K/P boundary (El Kef area, Tunisia)

    Science.gov (United States)

    Dill, H. G.; Weiss, W.; Botz, R.; Dohrmann, R.

    2011-06-01

    The El Kef area, Tunisia, is host of the official stratotype of the K/P boundary and of a complex metallic and non-metallic mineralization at Djebel Sekarna, encompassing syn(dia)genetic shale- and carbonate-hosted Zn-P and epigenetic Pb-Zn-Ba ore mineralizations. Micropaleontological, geological, mineralogical, and chemical studies (major and minor elements, C- and O-isotopes) of Upper Santonian to Lower Eocene calcareous-siliciclastic sediments resulted in a subdivision of this mineralization into eight mineralizing stages. Stages 1 and 2 (late Cretaceous-early Paleogene) are representative of syn(diagenetic) shale- and carbonate-hosted sulfidic and siliceous (Fe)-Zn-P mineralization deposited in shallow marine to slightly brackish sediments. Stages 3-5 (early Eocene respectively—pre- and post- Nummulites involutus-exilis zones) are representatives of epigenetic sulfidic and sulfatic (Fe)-Zn-Pb-Ba mineralizations at temperatures as high as 170/200°C and stages 6 and 7 (early Eocene respectively—post- Alveolina oblonga zone) cover the non-sulfidic Zn-(Pb) mineralization at temperatures as high as 60°C which is transitional from hypogene into supergene mineralization ("epithermal calamine deposits"). Stage 8 represents alteration of the pre-existing mineral assemblages in course of the Holocene weathering. The Cretaceous through Paleogene aquatic system is characterized by a poisoning of the sea with base metals, mainly Zn, and the atmosphere was chocked with clouds of fine-grained volcanic ejecta. Both processes contributed to the build-up of Zn-(Pb) deposits and vast, but uneconomic bentonitic clay deposits around the K/P boundary. Ore mineralization in the El Kef area is a multiple-phase process which reached its climax during the early Eocene as indicated by the large foram zones. These inorganic concentration processes resulting in the formation of mineral deposits had obviously also a negative effect on the long-term course of regional Earth

  1. Investigating the specific core genetic-and-epigenetic networks of cellular mechanisms involved in human aging in peripheral blood mononuclear cells.

    Science.gov (United States)

    Li, Cheng-Wei; Wang, Wen-Hsin; Chen, Bor-Sen

    2016-02-23

    Aging is an inevitable part of life for humans, and slowing down the aging process has become a main focus of human endeavor. Here, we applied a systems biology approach to construct protein-protein interaction networks, gene regulatory networks, and epigenetic networks, i.e. genetic and epigenetic networks (GENs), of elderly individuals and young controls. We then compared these GENs to extract aging mechanisms using microarray data in peripheral blood mononuclear cells, microRNA (miRNA) data, and database mining.The core GENs of elderly individuals and young controls were obtained by applying principal network projection to GENs based on Principal Component Analysis. By comparing the core networks, we identified that to overcome the accumulated mutation of genes in the aging process the transcription factor JUN can be activated by stress signals, including the MAPK signaling, T-cell receptor signaling, and neurotrophin signaling pathways through DNA methylation of BTG3, G0S2, and AP2B1 and the regulations of mir-223 let-7d, and mir-130a. We also address the aging mechanisms in old men and women. Furthermore, we proposed that drugs designed to target these DNA methylated genes or miRNAs may delay aging. A multiple drug combination comprising phenylalanine, cholesterol, and palbociclib was finally designed for delaying the aging process. PMID:26895224

  2. Nutritional Epigenetics

    Directory of Open Access Journals (Sweden)

    L. Preston Mercer

    2013-12-01

    Full Text Available Questions concerning the fundamental effects of nutrition on gene function are now being elucidated as the human genome project has been completed. Nutritional genomics seeks to expand the use of foods to achieve human genetic potential, while reducing the risk of diseases. As issues such as nutrigenomics (dietary influence on gene function and nutrigenetics (genomic reaction to diet are unraveled, thepotential for personalized nutrition becomes attainable. It has been stated that “genomics is to the 21st century what infectious disease was to the 20th century”. The nucleotide sequence of DNA was once seen as the only mechanism by which genetic information could be transmitted between generations. Phenotypic variation resulted from recombination and, occasionally, genetic mutation. This widely accepted concept is now undergoing modification as evidence builds to support the idea that reversible, heritable changes in gene function - termed “epigenetics”- can occur without a change in the sequence of nuclear DNA (i.e., non-Mendelian inheritance. The word epigenetics is of Greek origin and literallymeans over and above (epi the genome. The terminology“same genome, different epigenome” has been demonstrated in several experiments. As research and understanding advances, dietary advice based on the human genome will become more prevalent and new pharmacological interventions may be developed.

  3. 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.

  4. Epigenetic mechanisms in penile carcinoma

    DEFF Research Database (Denmark)

    Kuasne, Hellen; Marchi, Fabio Albuquerque; Rogatto, Silvia Regina;

    2013-01-01

    Penile carcinoma (PeCa) represents an important public health problem in poor and developing countries. Despite its unpredictable behavior and aggressive treatment, there have only been a few reports regarding its molecular data, especially epigenetic mechanisms. The functional diversity in diffe......Penile carcinoma (PeCa) represents an important public health problem in poor and developing countries. Despite its unpredictable behavior and aggressive treatment, there have only been a few reports regarding its molecular data, especially epigenetic mechanisms. The functional diversity...... in different cell types is acquired by chromatin modifications, which are established by epigenetic regulatory mechanisms involving DNA methylation, histone acetylation, and miRNAs. Recent evidence indicates that the dysregulation in these processes can result in the development of several diseases, including...... cancer. Epigenetic alterations, such as the methylation of CpGs islands, may reveal candidates for the development of specific markers for cancer detection, diagnosis and prognosis. There are a few reports on the epigenetic alterations in PeCa, and most of these studies have only focused on alterations...

  5. Epigenetic Regulation of Cancer-Associated Genes in Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Mi Jeong Kwon

    2011-01-01

    Full Text Available The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the DNA hypomethylation of some genes. Recently, we reported that the overexpression of cancer-promoting genes in ovarian cancer is associated with the loss of repressive histone modifications. This discovery suggested that epigenetic derepression may contribute to ovarian tumorigenesis by constituting a possible mechanism for the overexpression of oncogenes or cancer-promoting genes in tumors. The emerging importance of epigenetic aberrations in tumor initiation and in the regulation of cancer-initiating cells, suggests that epigenetically regulated genes may be promising therapeutic targets and biomarkers. Given that the current challenges in ovarian cancer include the identification of biomarkers for early cancer detection and the discovery of novel therapeutic targets for patients with recurrent malignancies undergoing chemotherapy, understanding the epigenetic changes that occur in ovarian cancer is crucial. This review looks at epigenetic mechanisms involved in the regulation of cancer-associated genes, including the contribution of epigenetic derepression to the activation of cancer-associated genes in ovarian cancer. In addition, possible epigenetic therapies targeting epigenetically dysregulated genes are discussed. A better understanding of the epigenetic changes in ovarian cancer will contribute to the improvement of patient outcomes.

  6. Epigenetic: A missing paradigm in cellular and molecular pathways of sulfur mustard lung: a prospective and comparative study

    Directory of Open Access Journals (Sweden)

    Saber Imani

    2015-08-01

    Full Text Available Sulfur mustard (SM, bis- (2-chloroethyl sulphide is a chemical warfare agent that causes DNA alkylation, protein modification and membrane damage. SM can trigger several molecular pathways involved in inflammation and oxidative stress, which cause cell necrosis and apoptosis, and loss of cells integrity and function. Epigenetic regulation of gene expression is a growing research topic and is addressed by DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs expression. It seems SM can induce the epigenetic modifications that are translated into change in gene expression. Classification of epigenetic modifications long after exposure to SM would clarify its mechanism and paves a better strategy for the treatment of SM-affected patients. In this study, we review the key aberrant epigenetic modifications that have important roles in chronic obstructive pulmonary disease (COPD and compared with mustard lung.

  7. Some inconvenient truths about biosignatures involving two chemical species on Earth-like exoplanets

    CERN Document Server

    Rein, Hanno; Spiegel, David S

    2014-01-01

    The detection of strong thermochemical disequilibrium in the atmosphere of an extrasolar planet is thought to be a potential biosignature. In this article we present a new kind of false positive that can mimic a disequilibrium or any other biosignature that involves two chemical species. We consider a scenario where the exoplanet hosts a moon that has its own atmosphere and neither of the atmospheres is in chemical disequilibrium. Our results show that the integrated spectrum of the planet and the moon closely resembles that of a single object in strong chemical disequilibrium. We derive a firm limit on the maximum spectral resolution that can be obtained for both directly-imaged and transiting planets. The spectral resolution of even idealized space-based spectrographs that might be achievable in the next several decades is in general insufficient to break the degeneracy. Both chemical species can only be definitively confirmed in the same object if absorption features of both chemicals can be unambiguously ...

  8. Heritable epigenetic variation among maize inbreds.

    Directory of Open Access Journals (Sweden)

    Steve R Eichten

    2011-11-01

    Full Text Available Epigenetic variation describes heritable differences that are not attributable to changes in DNA sequence. There is the potential for pure epigenetic variation that occurs in the absence of any genetic change or for more complex situations that involve both genetic and epigenetic differences. Methylation of cytosine residues provides one mechanism for the inheritance of epigenetic information. A genome-wide profiling of DNA methylation in two different genotypes of Zea mays (ssp. mays, an organism with a complex genome of interspersed genes and repetitive elements, allowed the identification and characterization of examples of natural epigenetic variation. The distribution of DNA methylation was profiled using immunoprecipitation of methylated DNA followed by hybridization to a high-density tiling microarray. The comparison of the DNA methylation levels in the two genotypes, B73 and Mo17, allowed for the identification of approximately 700 differentially methylated regions (DMRs. Several of these DMRs occur in genomic regions that are apparently identical by descent in B73 and Mo17 suggesting that they may be examples of pure epigenetic variation. The methylation levels of the DMRs were further studied in a panel of near-isogenic lines to evaluate the stable inheritance of the methylation levels and to assess the contribution of cis- and trans- acting information to natural epigenetic variation. The majority of DMRs that occur in genomic regions without genetic variation are controlled by cis-acting differences and exhibit relatively stable inheritance. This study provides evidence for naturally occurring epigenetic variation in maize, including examples of pure epigenetic variation that is not conditioned by genetic differences. The epigenetic differences are variable within maize populations and exhibit relatively stable trans-generational inheritance. The detected examples of epigenetic variation, including some without tightly linked genetic

  9. 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.

  10. Epigenetics, Behaviour, and Health

    Directory of Open Access Journals (Sweden)

    Szyf Moshe

    2008-03-01

    Full Text Available The long-term effects of behaviour and environmental exposures, particularly during childhood, on health outcomes are well documented. Particularly thought provoking is the notion that exposures to different social environments have a long-lasting impact on human physical health. However, the mechanisms mediating the effects of the environment are still unclear. In the last decade, the main focus of attention was the genome, and interindividual genetic polymorphisms were sought after as the principal basis for susceptibility to disease. However, it is becoming clear that recent dramatic increases in the incidence of certain human pathologies, such as asthma and type 2 diabetes, cannot be explained just on the basis of a genetic drift. It is therefore extremely important to unravel the molecular links between the "environmental" exposure, which is believed to be behind this emerging incidence in certain human pathologies, and the disease's molecular mechanisms. Although it is clear that most human pathologies involve long-term changes in gene function, these might be caused by mechanisms other than changes in the deoxyribonucleic acid (DNA sequence. The genome is programmed by the epigenome, which is composed of chromatin and a covalent modification of DNA by methylation. It is postulated here that "epigenetic" mechanisms mediate the effects of behavioural and environmental exposures early in life, as well as lifelong environmental exposures and the susceptibility to disease later in life. In contrast to genetic sequence differences, epigenetic aberrations are potentially reversible, raising the hope for interventions that will be able to reverse deleterious epigenetic programming.

  11. Epigenetics in the Placenta

    OpenAIRE

    Maccani, Matthew A; Marsit, Carmen J.

    2009-01-01

    Epigenetics is focused on understanding the control of gene expression beyond what is encoded in the sequence of DNA. Central to growing interest in the field is the hope that more can be learned about the epigenetic regulatory mechanisms underlying processes of human development and disease. Researchers have begun to examine epigenetic alterations – such as changes in promoter DNA methylation, genomic imprinting, and expression of miRNA – to learn more about epigenetic regulation in the plac...

  12. Epigenetic disruption of cell signaling in nasopharyngeal carcinoma

    Institute of Scientific and Technical Information of China (English)

    Li-Li Li; Xing-Sheng Shu; Zhao-Hui Wang; Ya Cao; Qian Tao

    2011-01-01

    Nasopharyngeal carcinoma (NPC) is a malignancy with remarkable ethnic and geographic distribution in southern China and Southeast Asia. Alternative to genetic changes, aberrant epigenetic events disrupt multiple genes involved in cell signaling pathways through DNA methylation of promoter CpG islands and/ or histone modifications. These epigenetic alterations grant cell growth advantage and contribute to the initiation and progression of NPC. In this review, we summariye the epigenetic deregulation of cell signaling in NPC tumorigenesis and highlight the importance of identifying epigenetic cell signaling regulators in NPC research. Developing pharmacologic strategies to reverse the epigenetic-silencing of cell signaling regulators might thus be useful to NPC prevention and therapy.

  13. Possible Involvement of Standardized Bacopa monniera Extract (CDRI-08) in Epigenetic Regulation of reelin and Brain-Derived Neurotrophic Factor to Enhance Memory

    Science.gov (United States)

    Preethi, Jayakumar; Singh, Hemant K.; Rajan, Koilmani E.

    2016-01-01

    Bacopa monniera extract (CDRI-08; BME) has been known to improve learning and memory, and understanding the molecular mechanisms may help to know its specificity. We investigated whether the BME treatment alters the methylation status of reelin and brain-derived neurotropic factor (BDNF) to enhance the memory through the interaction of N-methyl-D-aspartate receptor (NMDAR) with synaptic proteins. Rat pups were subjected to novel object recognition test following daily oral administration of BME (80 mg/kg) in 0.5% gum acacia (per-orally, p.o.; PND 15–29)/three doses of 5-azacytidine (5-azaC; 3.2 mg/kg) in 0.9% saline (intraperitoneally, i.p.) on PND-30. After the behavioral test, methylation status of reelin, BDNF and activation of NMDAR, and its interactions with synaptic proteins were tested. Rat pups treated with BME/5-azaC showed higher discrimination towards novel objects than with old objects during testing. Further, we observed an elevated level of unmethylated DNA in reelin and BDNF promoter region. Up-regulated reelin along with the splice variant of apolipoprotein E receptor 2 (ApoER 2, ex 19) form a cluster and activate NMDAR through disabled adopter protein-1 (DAB1) to enhance BDNF. Observed results suggest that BME regulate reelin epigenetically, which might enhance NMDAR interactions with synaptic proteins and induction of BDNF. These changes may be linked with improved novel object recognition memory.

  14. The Role of Redox Signaling in Epigenetics and Cardiovascular Disease

    OpenAIRE

    Kim, Gene H.; Ryan, John J.; Archer, Stephen L.

    2013-01-01

    Significance: The term epigenetics refers to the changes in the phenotype and gene expression that occur without alterations in the DNA sequence. There is a rapidly growing body of evidence that epigenetic modifications are involved in the pathological mechanisms of many cardiovascular diseases (CVDs), which intersect with many of the pathways involved in oxidative stress. Recent Advances: Most studies relating epigenetics and human pathologies have focused on cancer. There has been a limited...

  15. Epigenetics and Nutritional Environmental Signals

    OpenAIRE

    Mazzio, Elizabeth A.; Soliman, Karam F. A.

    2014-01-01

    All terrestrial life is influenced by multi-directional flows of information about its environment, enabling malleable phenotypic change through signals, chemical processes, or various forms of energy that facilitate acclimatization. Billions of biological co-inhabitants of the earth, including all plants and animals, collectively make up a genetic/epigenetic ecosystem by which adaptation/survival (inputs and outputs) are highly interdependent on one another. As an ecosystem, the solar system...

  16. 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.

  17. 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. PMID:27212125

  18. 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....

  19. Stemming Epigenetics in Marine Stramenopiles

    OpenAIRE

    Maumus, Florian; Rabinowicz, Pablo; Bowler, Chris; Rivarola, Maximo

    2011-01-01

    Epigenetics include DNA methylation, the modification of histone tails that affect chromatin states, and small RNAs that are involved in the setting and maintenance of chromatin modifications. Marine stramenopiles (MAS), which are a diverse assemblage of algae that acquired photosynthesis from secondary endosymbiosis, include single-celled organisms such as diatoms as well as multicellular forms such as brown algae. The recent publication of two diatom genomes that diverged ~90 million years ...

  20. Epigenetic Mechanisms of Drug Addiction

    OpenAIRE

    Nestler, Eric J.

    2013-01-01

    Drug addiction involves potentially life-long behavioral abnormalities that are caused in vulnerable individuals by repeated exposure to a drug of abuse. The persistence of these behavioral changes suggests that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. Work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving lasting changes in gene expression in diverse tissues,...

  1. Natural indoles, indole-3-carbinol and 3,3′-diindolymethane, inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression

    Energy Technology Data Exchange (ETDEWEB)

    Busbee, Philip B.; Nagarkatti, Mitzi; Nagarkatti, Prakash S., E-mail: prakash@mailbox.sc.edu

    2014-01-01

    Staphylococcal enterotoxin B (SEB) is a potent exotoxin produced by the Staphylococcus aureus. This toxin is classified as a superantigen because of its ability to directly bind with MHC-II class molecules followed by activation of a large proportion of T cells bearing specific Vβ-T cell receptors. Commonly associated with classic food poisoning, SEB has also been shown to induce toxic shock syndrome, and is also considered to be a potential biological warfare agent because it is easily aerosolized. In the present study, we assessed the ability of indole-3-carbinol (I3C) and one of its byproducts, 3,3′-diindolylmethane (DIM), found in cruciferous vegetables, to counteract the effects of SEB-induced activation of T cells in mice. Both I3C and DIM were found to decrease the activation, proliferation, and cytokine production by SEB-activated Vβ8{sup +} T cells in vitro and in vivo. Interestingly, inhibitors of histone deacetylase class I (HDAC-I), but not class II (HDAC-II), showed significant decrease in SEB-induced T cell activation and cytokine production, thereby suggesting that epigenetic modulation plays a critical role in the regulation of SEB-induced inflammation. In addition, I3C and DIM caused a decrease in HDAC-I but not HDAC-II in SEB-activated T cells, thereby suggesting that I3C and DIM may inhibit SEB-mediated T cell activation by acting as HDAC-I inhibitors. These studies not only suggest for the first time that plant-derived indoles are potent suppressors of SEB-induced T cell activation and cytokine storm but also that they may mediate these effects by acting as HDAC inhibitors. - Highlights: • I3C and DIM reduce SEB-induced T cell activation and inflammatory cytokines. • Inhibiting class I HDACs reduces T cell activation and inflammatory cytokines. • Inhibiting class II HDACs increases T cell activation and inflammatory cytokines. • I3C and DIM selectively reduce mRNA expression of class I HDACs. • Novel use and mechanism to counteract

  2. Natural indoles, indole-3-carbinol and 3,3′-diindolymethane, inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression

    International Nuclear Information System (INIS)

    Staphylococcal enterotoxin B (SEB) is a potent exotoxin produced by the Staphylococcus aureus. This toxin is classified as a superantigen because of its ability to directly bind with MHC-II class molecules followed by activation of a large proportion of T cells bearing specific Vβ-T cell receptors. Commonly associated with classic food poisoning, SEB has also been shown to induce toxic shock syndrome, and is also considered to be a potential biological warfare agent because it is easily aerosolized. In the present study, we assessed the ability of indole-3-carbinol (I3C) and one of its byproducts, 3,3′-diindolylmethane (DIM), found in cruciferous vegetables, to counteract the effects of SEB-induced activation of T cells in mice. Both I3C and DIM were found to decrease the activation, proliferation, and cytokine production by SEB-activated Vβ8+ T cells in vitro and in vivo. Interestingly, inhibitors of histone deacetylase class I (HDAC-I), but not class II (HDAC-II), showed significant decrease in SEB-induced T cell activation and cytokine production, thereby suggesting that epigenetic modulation plays a critical role in the regulation of SEB-induced inflammation. In addition, I3C and DIM caused a decrease in HDAC-I but not HDAC-II in SEB-activated T cells, thereby suggesting that I3C and DIM may inhibit SEB-mediated T cell activation by acting as HDAC-I inhibitors. These studies not only suggest for the first time that plant-derived indoles are potent suppressors of SEB-induced T cell activation and cytokine storm but also that they may mediate these effects by acting as HDAC inhibitors. - Highlights: • I3C and DIM reduce SEB-induced T cell activation and inflammatory cytokines. • Inhibiting class I HDACs reduces T cell activation and inflammatory cytokines. • Inhibiting class II HDACs increases T cell activation and inflammatory cytokines. • I3C and DIM selectively reduce mRNA expression of class I HDACs. • Novel use and mechanism to counteract SEB

  3. Some inconvenient truths about biosignatures involving two chemical species on Earth-like exoplanets.

    Science.gov (United States)

    Rein, Hanno; Fujii, Yuka; Spiegel, David S

    2014-05-13

    The detection of strong thermochemical disequilibrium in the atmosphere of an extrasolar planet is thought to be a potential biosignature. In this article we present a previously unidentified kind of false positive that can mimic a disequilibrium or any other biosignature that involves two chemical species. We consider a scenario where the exoplanet hosts a moon that has its own atmosphere and neither of the atmospheres is in chemical disequilibrium. Our results show that the integrated spectrum of the planet and the moon closely resembles that of a single object in strong chemical disequilibrium. We derive a firm limit on the maximum spectral resolution that can be obtained for both directly imaged and transiting planets. The spectral resolution of even idealized space-based spectrographs that might be achievable in the next several decades is in general insufficient to break the degeneracy. Both chemical species can only be definitively confirmed in the same object if absorption features of both chemicals can be unambiguously identified and their combined depth exceeds 100%. PMID:24778224

  4. Prospects for Epigenetic Epidemiology

    OpenAIRE

    Debra L Foley; Craig, Jeffrey M; Morley, Ruth; Olsson, Craig J.; Dwyer, Terence; Smith, Katherine; Saffery, Richard

    2009-01-01

    Epigenetic modification can mediate environmental influences on gene expression and can modulate the disease risk associated with genetic variation. Epigenetic analysis therefore holds substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. The spatial and temporal variance in epigenetic profile is of particular relevance for developmental epidemiology and the study of aging, including the variable age at onset for man...

  5. 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 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...

  6. Epigenetics in liver disease

    OpenAIRE

    Mann, Derek A.

    2014-01-01

    Epigenetics is a term that encompasses a variety of regulatory processes that are able to crosstalk in order to influence gene expression and cell phenotype in response to environmental cues. A deep understanding of epigenetics offers the potential for fresh insights into the basis for complex chronic diseases and improved diagnostic and prognostic tools. Moreover, as epigenetic modifications are highly plastic and responsive to the environment, there is much excitement around the theme of ep...

  7. Epigenetic mechanisms of drug addiction.

    Science.gov (United States)

    Nestler, Eric J

    2014-01-01

    Drug addiction involves potentially life-long behavioral abnormalities that are caused in vulnerable individuals by repeated exposure to a drug of abuse. The persistence of these behavioral changes suggests that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. Work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving lasting changes in gene expression in diverse tissues, including brain. This has prompted recent research aimed at characterizing the influence of epigenetic regulatory events in mediating the lasting effects of drugs of abuse on the brain in animal models of drug addiction. This review provides a progress report of this still early work in the field. As will be seen, there is robust evidence that repeated exposure to drugs of abuse induces changes within the brain's reward regions in three major modes of epigenetic regulation-histone modifications such as acetylation and methylation, DNA methylation, and non-coding RNAs. In several instances, it has been possible to demonstrate directly the contribution of such epigenetic changes to addiction-related behavioral abnormalities. Studies of epigenetic mechanisms of addiction are also providing an unprecedented view of the range of genes and non-genic regions that are affected by repeated drug exposure and the precise molecular basis of that regulation. Work is now needed to validate key aspects of this work in human addiction and evaluate the possibility of mining this information to develop new diagnostic tests and more effective treatments for addiction syndromes. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID:23643695

  8. [Epigenetics and cancer].

    Science.gov (United States)

    Deltour, Sophie; Chopin, Valérie; Leprince, Dominique

    2005-04-01

    Epigenetics is defined as "the study of mitotically and/or meiotically heritable changes in gene expression that cannot be explained by changes in the DNA sequence". Setting up the epigenetic program is crucial for correct development and its stable inheritance throughout its lifespan is essential for the maintenance of the tissue- and cell-specific functions of the organism. For many years, the genetic causes of cancer have hold centre stage. However, the recent wealth of information about the molecular mechanisms which, by modulating the chromatin structure, can regulate gene expression has high-lighted the predominant role of epigenetic modifications in the initiation and progression of numerous pathologies, including cancer. The nucleosome is the major target of these epigenetic regulation mechanisms. They include a series of tightly interconnected steps which starting with the setting ("writing") of the epigenetic mark till its "reading" and interpretation will result in long-term gene regulation. The major epigenetic changes associated with tumorigenesis are aberrant DNA methylation of CpG islands located in the promoter region of tumor suppressor gene, global genomic hypomethylation and covalent modifications of histone N-terminal tails which are protruding out from the nucleosome core. In sharp contrast with genetic modifications, epigenetic modifications are highly dynamic and reversible. The characterization of specific inhibitors directed against some key epigenetic players has opened a new and promising therapeutic avenue, the epigenetic therapy, since some inhibitors are already used in clinical trials. PMID:15811306

  9. Epigenetic mechanisms and gastrointestinal development

    Science.gov (United States)

    This review considers the hypothesis that nutrition during infancy affects developmental epigenetics in the gut, causing metabolic imprinting of gastrointestinal (GI) structure and function. Fundamentals of epigenetic gene regulation are reviewed, with an emphasis on the epigenetic mechanism of DNA ...

  10. Epileptogenesis: Can the Science of Epigenetics Give Us Answers?

    OpenAIRE

    Lubin, Farah D.

    2012-01-01

    Epigenetic mechanisms are regulatory processes that control gene expression changes involved in multiple aspects of neuronal function, including central nervous system development, synaptic plasticity, and memory. Recent evidence indicates that dysregulation of epigenetic mechanisms occurs in several human epilepsy syndromes. Despite this discovery of a potential role for epigenetic mechanisms in epilepsy, few studies have fully explored their contribution to the process of epilepsy developme...

  11. Past, present, and future of epigenetics applied to livestock breeding

    OpenAIRE

    González-Recio, Oscar; Toro, Miguel A; Bach, Alex

    2015-01-01

    This article reviews the concept of Lamarckian inheritance and the use of the term epigenetics in the field of animal genetics. Epigenetics was first coined by Conrad Hal Waddington (1905–1975), who derived the term from the Aristotelian word epigenesis. There exists some controversy around the word epigenetics and its broad definition. It includes any modification of the expression of genes due to factors other than mutation in the DNA sequence. This involves DNA methylation, post-translatio...

  12. Epigenetics of multiple sclerosis: an updated review.

    Science.gov (United States)

    Küçükali, Cem İsmail; Kürtüncü, Murat; Çoban, Arzu; Çebi, Merve; Tüzün, Erdem

    2015-06-01

    Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized with autoimmune response against myelin proteins and progressive axonal loss. The heterogeneity of the clinical course and low concordance rates in monozygotic twins have indicated the involvement of complex heritable and environmental factors in MS pathogenesis. MS is more often transmitted to the next generation by mothers than fathers suggesting an epigenetic influence. One of the possible reasons of this parent-of-origin effect might be the human leukocyte antigen-DRB1*15 allele, which is the major risk factor for MS and regulated by epigenetic mechanisms such as DNA methylation and histone deacetylation. Moreover, major environmental risk factors for MS, vitamin D deficiency, smoking and Ebstein-Barr virus are all known to exert epigenetic changes. In the last few decades, compelling evidence implicating the role of epigenetics in MS has accumulated. Increased or decreased acetylation, methylation and citrullination of genes regulating the expression of inflammation and myelination factors appear to be particularly involved in the epigenetics of MS. Although much less is known about epigenetic factors causing neurodegeneration, epigenetic mechanisms regulating axonal loss, apoptosis and mitochondrial dysfunction in MS are in the process of identification. Additionally, expression levels of several microRNAs (miRNAs) (e.g., miR-155 and miR-326) are increased in MS brains and potential mechanisms by which these factors might influence MS pathogenesis have been described. Certain miRNAs may also be potentially used as diagnostic biomarkers in MS. Several reagents, especially histone deacetylase inhibitors have been shown to ameliorate the symptoms of experimental allergic encephalomyelitis. Ongoing efforts in this field are expected to result in characterization of epigenetic factors that can be used in prediction of treatment responsive MS patients, diagnostic screening panels

  13. Molecular cloning and chemical synthesis of a region of platelet glycoprotein IIb involved in adhesive function.

    OpenAIRE

    Loftus, J C; Plow, E F; Frelinger, A.L.; D'Souza, S E; Dixon, D; Lacy, J.; Sorge, J; Ginsberg, M H

    1987-01-01

    Membrane glycoprotein (GP) IIb-IIIa is a component of a platelet adhesive protein receptor. A region of the heavy chain of GPIIb, defined by the monoclonal antibody PMI-1, is involved in adhesion receptor function. We have localized and chemically synthesized this region of GPIIb. A cDNA clone that directs the synthesis of a fusion protein reactive with the PMI-1 antibody was isolated from a phage lambda gt11 expression library constructed with mRNA from an erythroleukemia (HEL) cell line. Th...

  14. 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. PMID:26523718

  15. Longevity: epigenetic and biomolecular aspects.

    Science.gov (United States)

    Taormina, Giusi; Mirisola, Mario G

    2015-04-01

    Many aging theories and their related molecular mechanisms have been proposed. Simple model organisms such as yeasts, worms, fruit flies and others have massively contributed to their clarification, and many genes and pathways have been associated with longevity regulation. Among them, insulin/IGF-1 plays a key and evolutionary conserved role. Interestingly, dietary interventions can modulate this pathway. Calorie restriction (CR), intermittent fasting, and protein and amino acid restriction prolong the lifespan of mammals by IGF-1 regulation. However, some recent findings support the hypothesis that the long-term effects of diet also involve epigenetic mechanisms. In this review, we describe the best characterized aging pathways and highlight the role of epigenetics in diet-mediated longevity. PMID:25883209

  16. 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.

  17. 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

  18. Epigenetic regulation in alcoholic liver disease

    Institute of Scientific and Technical Information of China (English)

    Pranoti Mandrekar

    2011-01-01

    Alcoholic liver disease (ALD) is characterized by steatosis or fat deposition in the liver and inflammation, which leads to cirrhosis and hepatocellular carcinoma. Induction of target genes without involving changes in DNA sequence seems to contribute greatly to liver injury. Chromatin modifications including alterations in histones and DNA, as well as post-transcriptional changes collectively referred to as epigenetic effects are altered by alcohol. Recent studies have pointed to a significant role for epigenetic mechanisms at the nucleosomal level influencing gene expression and disease outcome in ALD. Specifically, epigenetic alterations by alcohol include histone modifications such as changes in acetylation and phosphorylation, hypomethylation of DNA, and alterations in miRNAs. These modifications can be induced by alcohol-induced oxidative stress that results in altered recruitment of transcriptional machinery and abnormal gene expression. Delineating these mechanisms in initiation and progression of ALD is becoming a major area of interest. This review summarizes key epigenetic mechanisms that are dysregulated by alcohol in the liver. Alterations by alcohol in histone and DNA modifications, enzymes related to histone acetylation such as histone acetyltransferases, histone deacetylases and sirtuins, and methylation enzymes such as DNA methyltransferases are discussed. Chromatin modifications and miRNA alterations that result in immune cell dysfunction contributing to inflammatory cytokine production in ALD is reviewed. Finally, the role of alcohol-mediated oxidative stress in epigenetic regulation in ALD is described. A better understanding of these mechanisms is crucial for designing novel epigenetic based therapies to ameliorate ALD.

  19. 76 FR 76935 - Impact of Implementing the Chemical Weapons Convention (CWC) on Commercial Activities Involving...

    Science.gov (United States)

    2011-12-09

    ... Bureau of Industry and Security Impact of Implementing the Chemical Weapons Convention (CWC) on... implementation of the Chemical Weapons Convention (CWC), through the Chemical Weapons Convention Implementation Act (CWCIA), and the Chemical Weapons Convention Regulations (CWCR), has had on commercial...

  20. The Epigenetic Reprogramming Roadmap in Generation of iPSCs from Somatic Cells

    DEFF Research Database (Denmark)

    Brix, Jacob; Zhou, Yan; Luo, Yonglun

    2015-01-01

    Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is a comprehensive epigenetic process involving genome-wide modifications of histones and DNA methylation. This process is often incomplete, which subsequently affects iPSC reprograming, pluripotency, and differentiation...... capacity. Here we review the epigenetic changes with a focus on histone modification (methylation and acetylation) and DNA modification (methylation) during iPSC induction. We look at changes in specific epigenetic signatures, aberrations and epigenetic memory during reprogramming and small molecules...... influencing the epigenetic reprogramming of somatic cells. Finally, we discuss how to improve iPSC generation and pluripotency through epigenetic manipulations....

  1. Epigenetic understanding of gene-environment interactions in psychiatric disorders: a new concept of clinical genetics

    OpenAIRE

    Kubota Takeo; Miyake Kunio; Hirasawa Takae

    2012-01-01

    Abstract Epigenetics is a mechanism that regulates gene expression independently of the underlying DNA sequence, relying instead on the chemical modification of DNA and histone proteins. Although environmental and genetic factors were thought to be independently associated with disorders, several recent lines of evidence suggest that epigenetics bridges these two factors. Epigenetic gene regulation is essential for normal development, thus defects in epigenetics cause various rare congenital ...

  2. Epigenetic involvement of Alien/ESET complex in thyroid hormone-mediated repression of E2F1 gene expression and cell proliferation

    International Nuclear Information System (INIS)

    Highlights: ► Corepressor Alien interacts with histone methyltransferase ESET in vivo. ► Alien/ESET complex is recruited to nTRE of T3-responsive gene by liganded TRβ1. ► ESET-mediated H3K9 methylation is required for liganded TRβ1-repressed transcription. ► ESET is involved in T3-repressed G1/S phase transition and proliferation. -- Abstract: The ligand-bound thyroid hormone receptor (TR) is known to repress via a negative TRE (nTRE) the expression of E2F1, a key transcription factor that controls the G1/S phase transition. Alien has been identified as a novel interacting factor of E2F1 and acts as a corepressor of E2F1. The detailed molecular mechanism by which Alien inhibits E2F1 gene expression remains unclear. Here, we report that the histone H3 lysine 9 (H3K9) methyltransferase (HMT) ESET is an integral component of the corepressor Alien complex and the Alien/ESET complex is recruited to both sites, the E2F1 and the nTRE site of the E2F1 gene while the recruitment to the negative thyroid hormone response element (nTRE) is induced by the ligand-bound TRβ1 within the E2F1 gene promoter. We show that, overexpression of ESET promotes, whereas knockdown of ESET releases, the inhibition of TRβ1-regulated gene transcription upon T3 stimulation; and H3K9 methylation is required for TRβ1-repressed transcription. Furthermore, depletion of ESET impairs thyroid hormone-repressed proliferation as well as the G1/S transition of the cell cycle. Taken together, our data indicate that ESET is involved in TRβ1-mediated transcription repression and provide a molecular basis of thyroid hormone-induced repression of proliferation.

  3. Review and hypothesis: syndromes with severe intrauterine growth restriction and very short stature--are they related to the epigenetic mechanism(s) of fetal survival involved in the developmental origins of adult health and disease?

    Science.gov (United States)

    Hall, Judith G

    2010-02-01

    Diagnosing the specific type of severe intrauterine growth restriction (IUGR) that also has post-birth growth restriction is often difficult. Eight relatively common syndromes are discussed identifying their unique distinguishing features, overlapping features, and those features common to all eight syndromes. Many of these signs take a few years to develop and the lifetime natural history of the disorders has not yet been completely clarified. The theory behind developmental origins of adult health and disease suggests that there are mammalian epigenetic fetal survival mechanisms that downregulate fetal growth, both in order for the fetus to survive until birth and to prepare it for a restricted extra-uterine environment, and that these mechanisms have long lasting effects on the adult health of the individual. Silver-Russell syndrome phenotype has recently been recognized to be related to imprinting/methylation defects. Perhaps all eight syndromes, including those with single gene mutation origin, involve the mammalian mechanism(s) of fetal survival downsizing. Insights into those mechanisms should provide avenues to understanding the natural history, the heterogeneity and possible therapy not only for these eight syndromes, but for the common adult diseases with which IUGR is associated. PMID:20101705

  4. Environmental Epigenetics: Potential Application in Human Health Risk Assessment

    Science.gov (United States)

    Although previous studies have shown a significant involvement of epigenetic dysregulation in human diseases, the applicability of epigenetic data in the current human health risk assessment paradigm is unclear. The goals of this study are to compare the relative sensitivities of...

  5. Scrutinizing the epigenetics revolution.

    Science.gov (United States)

    Meloni, Maurizio; Testa, Giuseppe

    2014-11-01

    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

  6. Models of epigenetics

    DEFF Research Database (Denmark)

    Alsing, Anne

    genomic material can show quiet diverse phenotypes characterized by organ speci c gene expression patterns. The mechanisms responsible for this phenotypic plasticity are characterized as epigenetic, as they in ict their e ect \\epi-" (Greek for \\above" or \\on top") of the genetic code. For a gene...... regulatory mechanism to be classi ed as epigenetic, it is required that it is self-sustainable in the sense that the governed gene expression or repression should prevail for the lifetime of the cell and must be inherited by possible daughter cells. An example of epigenetic di erentiation is the bistable...

  7. 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…

  8. Middle atmosphere heating by exothermic chemical reactions involving odd-hydrogen species

    Science.gov (United States)

    Mlynczak, Martin G.; Solomon, Susan

    1991-01-01

    The rate of heating which occurs in the middle atmosphere due to four exothermic reactions involving members of the odd-hydrogen family is calculated. The following reactions are considered: O + OH yields O2 + H; H + O2 + M yields HO2 + M; H + O3 yields OH + O2; and O + HO2 yields OH + O2. It is shown that the heating rates due to these reactions rival the oxygen-related heating rates conventionally considered in middle-atmosphere models. The conversion of chemical potential energy into molecular translational energy (heat) by these odd-hydrogen reactions is shown to be a significant energy source in the middle atmosphere that has not been previously considered.

  9. Sulfomethylated lignosulfonates as additives in oil recovery processes involving chemical recovery agents

    Energy Technology Data Exchange (ETDEWEB)

    Kalfoglou, G.

    1979-10-30

    A process for producing petroleum from subterranean formations is disclosed wherein production from the formation is obtained by driving a fluid from an injection well to a production well. The process involves injecting via the injection well into the formation an aqueous solution of sulfomethylated lignosulfonate salt as a sacrificial agent to inhibit the deposition of surfactant and/or polymer on the reservoir matrix. The process may best be carried out by injecting the sulfomethylated lignosulfonates into the formation through the injection well mixed with either a polymer, a surfactant solution and/or a micellar dispersion. This mixture would then be followed by a drive fluid such as water to push the chemicals to the production well.

  10. Sulfomethylated lignosulfonates as additives in oil recovery processes involving chemical recovery agents

    Energy Technology Data Exchange (ETDEWEB)

    Kalfoglou, G.

    1981-05-26

    A process for producing petroleum from subterranean formations is disclosed wherein production from the formation is obtained by driving a fluid from an injection well to a production well. The process involves injecting via the injection well into the formation an aqueous solution of sulfomethylated lignosulfonate salt as a sacrificial agent to inhibit the deposition of surfactant and/or polymer on the reservoir matrix. The process may best be carried out by injecting the sulfomethylated lignosulfonates into the formation through the injection well mixed with either a polymer, a surfactant solution and/or a micellar dispersion. This mixture would then be followed by a drive fluid such as water to push the chemicals to the production well.

  11. In-silico bonding schemes to encode chemical bonds involving sharing of electrons in molecular structures.

    Science.gov (United States)

    Punnaivanam, Sankar; Sathiadhas, Jerome Pastal Raj; Panneerselvam, Vinoth

    2016-05-01

    Encoding of covalent and coordinate covalent bonds in molecular structures using ground state valence electronic configuration is achieved. The bonding due to electron sharing in the molecular structures is described with five fundamental bonding categories viz. uPair-uPair, lPair-uPair, uPair-lPair, vPair-lPair, and lPair-lPair. The involvement of lone pair electrons and the vacant electron orbitals in chemical bonding are explained with bonding schemes namely "target vacant promotion", "source vacant promotion", "target pairing promotion", "source pairing promotion", "source cation promotion", "source pairing double bond", "target vacant occupation", and "double pairing promotion" schemes. The bonding schemes are verified with a chemical structure editor. The bonding in the structures like ylides, PCl5, SF6, IF7, N-Oxides, BF4(-), AlCl4(-) etc. are explained and encoded unambiguously. The encoding of bonding in the structures of various organic compounds, transition metals compounds, coordination complexes and metal carbonyls is accomplished. PMID:27041446

  12. [The meaning of epigenetics].

    Science.gov (United States)

    Hu, Kai

    2002-11-01

    Epigenetics, the term was introduced by Conrad H.Waddington, in 1942,he said that to compare genetics with epigenetics, the study of the processes by which genotype gives rise to phenotype. In 1987, Robin Holliday redefined epigenetic as "Nuclear inheritance which is not based on differences in DNA sequence". The author of this paper introduced that in Science,10 August 2001,there was a special collection of review articles focused on the topic of epigenetics. The new "histone code" hypothesis states that the highly modifiable amino termini could carry their own combinatorial codes to help control phenotype,and that part of this code is heritable. And in light of this hypothesis,researchers are approaching further possibilities in human biology and types of cancer and other diseases. PMID:15979980

  13. [Epigenetics in Parkinson's Disease].

    Science.gov (United States)

    Wüllner, U

    2016-07-01

    The genetic information encoded in the DNA sequence provides a blueprint of the entire organism. The epigenetic modifications, in particular DNA methylation and histone modifications, determine how and when this information is made available and define the specific gene transcription pattern of a given cell. Epigenetic modifications determine the functional differences of genetically identical cells in multicellular organisms and are important factors in various processes from embryonic development to learning and memory consolidation. DNA methylation patterns are altered by environmental conditions and some alterations are preserved through mitosis and meiosis. Thus, DNA methylation can mediate environmental impact on health and disease, contributes to the severity of diseases and probably contributes to the effects and side effects of drugs. In addition to the classical monogenic epigenetic diseases such as Prader-Willi syndrome and Rett syndrome, recent data point to an epigenetic component also in sporadic neuro-psychiatric disorders. PMID:27299943

  14. Epigenetics: Biology's Quantum Mechanics.

    Science.gov (United States)

    Jorgensen, Richard A

    2011-01-01

    The perspective presented here is that modern genetics is at a similar stage of development as were early formulations of quantum mechanics theory in the 1920s and that in 2010 we are at the dawn of a new revolution in genetics that promises to enrich and deepen our understanding of the gene and the genome. The interrelationships and interdependence of two views of the gene - the molecular biological view and the epigenetic view - are explored, and it is argued that the classical molecular biological view is incomplete without incorporation of the epigenetic perspective and that in a sense the molecular biological view has been evolving to include the epigenetic view. Intriguingly, this evolution of the molecular view toward the broader and more inclusive epigenetic view of the gene has an intriguing, if not precise, parallel in the evolution of concepts of atomic physics from Newtonian mechanics to quantum mechanics that are interesting to consider. PMID:22639577

  15. Epigenetics: Biology's Quantum Mechanics

    Directory of Open Access Journals (Sweden)

    Richard A Jorgensen

    2011-04-01

    Full Text Available The perspective presented here is that modern genetics is at a similar stage of development as were early formulations of quantum mechanics theory in the 1920's and that in 2010 we are at the dawn of a new revolution in genetics that promises to enrich and deepen our understanding of the gene and the genome. The interrelationships and interdependence of two views of the gene - the molecular biological view and the epigenetic view - are explored, and it is argued that the classical molecular biological view is incomplete without incorporation of the epigenetic perspective and that in a sense the molecular biological view has been evolving to include the epigenetic view. Intriguingly, this evolution of the molecular view toward the broader and more inclusive epigenetic view of the gene has an intriguing, if not precise, parallel in the evolution of concepts of atomic physics from Newtonian mechanics to quantum mechanics that are interesting to consider.

  16. Epigenetics and addiction.

    Science.gov (United States)

    Cadet, J L; McCoy, M T; Jayanthi, S

    2016-05-01

    Addictions are public health menaces. However, despite advances in addiction research, the cellular or molecular mechanisms that cause transition from recreational use to addiction remain to be elucidated. We have recently suggested that addiction may be secondary to long-term epigenetic modifications that determine the clinical course of substance use disorders. A better understanding of epigenetic mechanisms in animal models that mimic human conditions should help to usher in a new area of drug development against addiction. PMID:26841306

  17. Epigenetic Mechanisms of Depression

    OpenAIRE

    Nestler, Eric J.

    2014-01-01

    Growing evidence supports the hypothesis that epigenetics is a key mechanism through which environmental exposures interact with an individual’s genetic constitution to determine risk for depression throughout life.1 Epigenetics, in its broadest meaning, refers to stable changes in gene expression that are mediated via altered chromatin structure without modification of DNA sequence. According to this hypothesis, severe stress triggers changes—in vulnerable individuals—in chromatin structure ...

  18. Fatty acids and epigenetics

    OpenAIRE

    Burdge, Graham C; Lillycrop, Karen A.

    2014-01-01

    Purpose of review The purpose of this review is to assess the findings of recent studies on the effects of fatty acids on epigenetic process and the role of epigenetics in regulating fatty acid metabolism. Recent findings The DNA methylation status of the Fads2 promoter was increased in the liver of the offspring of mice fed an ?-linolenic acid-enriched diet during pregnancy. In rats, increasing total maternal fat intake during pregnancy and lactation induced persistent hypermethyl...

  19. Epigenetics of Lung Cancer

    OpenAIRE

    Langevin, Scott M; Kratzke, Robert A.; Kelsey, Karl T.

    2014-01-01

    Lung cancer is the leading cause of cancer-related mortality in the United States. Epigenetic alterations, including DNA methylation, histone modifications, and non-coding RNA expression, have widely been reported in the literature to play a major role in the genesis of lung cancer. The goal of this review is to summarize the common epigenetic changes associated with lung cancer to give some clarity to its etiology, and provide an overview of the potential translational applications of these ...

  20. Epigenetic Therapy in Human Choriocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Takai, Noriyuki, E-mail: takai@oita-u.ac.jp [Department of Obstetrics and Gynecology, Oita University Faculty of Medicine, Oita (Japan); Narahara, Hisashi [Department of Obstetrics and Gynecology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita 879-5593 (Japan)

    2010-09-10

    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.

  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 Therapy in Human Choriocarcinoma

    International Nuclear Information System (INIS)

    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

  3. Genetic alterations and epigenetic changes in hepatocarcinogenesis

    Directory of Open Access Journals (Sweden)

    Luz Stella Hoyos Giraldo

    2007-02-01

    Full Text Available

    Hepatocarcinogenesis as hepatocellular carcinoma (HCC is associated with background of chronic liver disease usually in association with cirrhosis, marked hepatic fibrosis, hepatitis B virus (HBV and/or hepatitis virus (HCV infection, chronic inflammation, Aflatoxin B1(AFB1 exposure, chronic alcoholism, metabolic disorder of the liver and necroinflamatory liver disease. Hepatocarcinogenesis involve two mechanisms, genetic alterations (with changes in the cell's DNA sequence and epigenetic changes (without changes in the cell's DNA sequence, but changes in the pattern of gene expression that can persist through one or more generations (somatic sense. Hepatocarcinogenesis is associated with activation of oncogenes and decreased expression of tumor suppressor genes (TSG; include those involved in cell cycle control, apoptosis, DNA repair, immortalization and angiogenesis. AFB1 is metabolized in the liver into a potent carcinogen, aflatoxin 8, 9-epoxide, which is detoxified by epoxide hydrolase (EPHX and glutathione S-transferase M1 (GSTM1.

    A failure of detoxification processes can allow to mutagenic metabolite to bind to DNA and inducing P53 mutation. Genetic polymorphism of EPHX and GSTM1 can make individuals more susceptible to AFB1. Epigenetic inactivation of GSTP1 by promoter hypermethylation plays a role in the development of HCC because, it leads that electrophilic metabolite increase DNA damage and mutations. HBV DNA integration into the host chromosomal DNA of hepatocytes has been detected in HBV-related HCC.

    DNA tumor viruses cause cancer mainly by interfering with cell cycle controls, and activating the cell's replication machinery by blocking the action of key TSG. HBx protein is a

  4. Importance of investigating epigenetic alterations for industry and regulators: An appraisal of current efforts by the Health and Environmental Sciences Institute.

    Science.gov (United States)

    Miousse, Isabelle R; Currie, Richard; Datta, Kaushik; Ellinger-Ziegelbauer, Heidrun; French, John E; Harrill, Alison H; Koturbash, Igor; Lawton, Michael; Mann, Derek; Meehan, Richard R; Moggs, Jonathan G; O'Lone, Raegan; Rasoulpour, Reza J; Pera, Renee A Reijo; Thompson, Karol

    2015-09-01

    Recent technological advances have led to rapid progress in the characterization of epigenetic modifications that control gene expression in a generally heritable way, and are likely involved in defining cellular phenotypes, developmental stages and disease status from one generation to the next. On November 18, 2013, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) held a symposium entitled "Advances in Assessing Adverse Epigenetic Effects of Drugs and Chemicals" in Washington, D.C. The goal of the symposium was to identify gaps in knowledge and highlight promising areas of progress that represent opportunities to utilize epigenomic profiling for risk assessment of drugs and chemicals. Epigenomic profiling has the potential to provide mechanistic information in toxicological safety assessments; this is especially relevant for the evaluation of carcinogenic or teratogenic potential and also for drugs that directly target epigenetic modifiers, like DNA methyltransferases or histone modifying enzymes. Furthermore, it can serve as an endpoint or marker for hazard characterization in chemical safety assessment. The assessment of epigenetic effects may also be approached with new model systems that could directly assess transgenerational effects or potentially sensitive stem cell populations. These would enhance the range of safety assessment tools for evaluating xenobiotics that perturb the epigenome. Here we provide a brief synopsis of the symposium, update findings since that time and then highlight potential directions for future collaborative efforts to incorporate epigenetic profiling into risk assessment. PMID:26134581

  5. 75 FR 69630 - Impact of Implementation of the Chemical Weapons Convention on Commercial Activities Involving...

    Science.gov (United States)

    2010-11-15

    ... Bureau of Industry and Security Impact of Implementation of the Chemical Weapons Convention on Commercial... implementation of the Chemical Weapons Convention (CWC), through the Chemical Weapons Convention Implementation Act (CWCIA) and the Chemical Weapons Convention Regulations (CWCR), has had on commercial...

  6. Defining the Functional Network of Epigenetic Regulators in Arabidopsis thaliana

    Institute of Scientific and Technical Information of China (English)

    Chongyuan Luo; Brittany G.Durgin; Naohide Watanabe; Eric Lam

    2009-01-01

    Development of ChiP-chip and ChlP-seq technologies has allowed genome-wide high-resolution profiling of chromatin-associated marks and binding sites for epigenetic regulators.However,signals for directing epigenetic modi fiers to their target sites are not understood.In this paper,we tested the hypothesis that genome location can affect the involvement of epigenetic regulators using Chromatin Charting (CC) Lines,which have an identical transgene construct inserted at different locations in the Arabidopsis genome.Four CC lines that showed evidence for epigenetic silencing of the luciferase reporter gene were transformed with RNAi vectors individually targeting epigenetic regulators LHP1,MOM1,CMT3,DRD1,DRM2,SUVH2,CLF,and HD1.Involvement of a particular epigenetic regulator in silencing the transgene locus in a CC line was determined by significant alterations in luciferase expression after suppression of the regulator's expression.Our results suggest that the targeting of epigenetic regulators can be influenced by genome location as well as sequence context.In addition,the relative importance of an epigenetic regulator can be influenced by tissue identity.We also report a novel approach to predict interactions between epigenetic regulators through clustering analysis of the regulators using alterations in gene expression of putative downstream targets,including endogenous loci and transgenes,in epigenetic mutants or RNAi lines.Our data support the existence of a complex and dynamic network of epigenetic regulators that serves to coordinate and control global gene expression in higher plants.

  7. Epigenetic learning in non-neural organisms

    Indian Academy of Sciences (India)

    Simona Ginsburg; Eva Jablonka

    2009-10-01

    Learning involves a usually adaptive response to an input (an external stimulus or the organism’s own behaviour) in which the input-response relation is memorized; some physical traces of the relation persist and can later be the basis of a more effective response. Using toy models we show that this characterization applies not only to the paradigmatic case of neural learning, but also to cellular responses that are based on epigenetic mechanisms of cell memory. The models suggest that the research agenda of epigenetics needs to be expanded.

  8. Diet and epigenetics in colon cancer

    Institute of Scientific and Technical Information of China (English)

    Minna Nystr(o)m; Marja Mutanen

    2009-01-01

    Over the past few years, evidence has accumulated indicating that apart from genetic alterations, epigenetic alterations, through e.g. aberrant promoter methylation, play a major role in the initiation and progression of colorectal cancer (CRC). Even in the hereditary colon cancer syndromes, in which the susceptibility is inherited dominantly, cancer develops only as the result of the progressive accumulation of genetic and epigenetic alterations. Diet can both prevent and induce colon carcinogenesis, for instance, through epigenetic changes, which regulate the homeostasis of the intestinal mucosa. Food-derived compounds are constantly present in the intestine and may shift cellular balance toward harmful outcomes, such as increased susceptibility to mutations. There is strong evidence that a major component of cancer risk may involve epigenetic changes in normal cells that increase the probability of cancer after genetic mutation. The recognition of epigenetic changes as a driving force in colorectal neoplasia would open new areas of research in disease epidemiology, risk assessment, and treatment, especially in mutation carriers who already have an inherited predisposition to cancer.(c) 2009 The WJG Press and Baishideng. All rights reserved.

  9. Epigenetic perturbations in aging stem cells.

    Science.gov (United States)

    Krauss, Sara Russo; de Haan, Gerald

    2016-08-01

    Stem cells maintain homeostasis in all regenerating tissues during the lifespan of an organism. Thus, age-related functional decline of such tissues is likely to be at least partially explained by molecular events occurring in the stem cell compartment. Some of these events involve epigenetic changes, which may dictate how an aging genome can lead to differential gene expression programs. Recent technological advances have made it now possible to assess the genome-wide distribution of an ever-increasing number of epigenetic marks. As a result, the hypothesis that there may be a causal role for an altered epigenome contributing to the functional decline of cells, tissues, and organs in aging organisms can now be explored. In this paper, we review recent developments in the field of epigenetic regulation of stem cells, and how this may contribute to aging. PMID:27229519

  10. Evidence of Epigenetic Mechanisms Affecting Carotenoids.

    Science.gov (United States)

    Arango, Jacobo; Beltrán, Jesús; Nuñez, Jonathan; Chavarriaga, Paul

    2016-01-01

    Epigenetic mechanisms are able to regulate plant development by generating non-Mendelian allelic interactions. An example of these are the responses to environmenal stimuli that result in phenotypic variability and transgression amongst important crop traits. The need to predict phenotypes from genotypes to understand the molecular basis of the genotype-by-environment interaction is a research priority. Today, with the recent discoveries in the field of epigenetics, this challenge goes beyond analyzing how DNA sequences change. Here we review examples of epigenetic regulation of genes involved in carotenoid synthesis and degradation, cases in which histone- and/or DNA-methylation, and RNA silencing at the posttranscriptional level affect carotenoids in plants. PMID:27485227

  11. Epigenetics in neonatal diseases

    Institute of Scientific and Technical Information of China (English)

    XU Xue-feng; DU Li-zhong

    2010-01-01

    Objective To review the role of epigenetic regulation in neonatal diseases and better understand Barker's "fetal origins of adult disease hypothesis".Data sources The data cited in this review were mainly obtained from the articles published in Medline/PubMed between January 1953 and December 2009.Study selection Articles associated with epigenetics and neonatal diseases were selected.Results There is a wealth of epidemiological evidence that lower birth weight is strongly correlated with an increased risk of adult diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular disease. This phenomenon of fetal origins of adult disease is strongly associated with fetal insults to epigenetic modifications of genes. A potential role of epigenetic modifications in congenital disorders, transient neonatal diabetes mellitus (TNDM), intrauterine growth retardation (IUGR), and persistent pulmonary hypertension of the newborn (PPHN) have been studied.Conclusions Acknowledgment of the role of these epigenetic modifications in neonatal diseases would be conducive to better understanding the pathogenesis of these diseases, and provide new insight for improved treatment and prevention of later adult diseases.

  12. Epigenetic: A missing paradigm in cellular and molecular pathways of sulfur mustard lung: a prospective and comparative study

    OpenAIRE

    Saber Imani; Yunes Panahi; Jafar Salimian; Junjiang Fu; Mostafa Ghanei

    2015-01-01

    Sulfur mustard (SM, bis- (2-chloroethyl) sulphide) is a chemical warfare agent that causes DNA alkylation, protein modification and membrane damage. SM can trigger several molecular pathways involved in inflammation and oxidative stress, which cause cell necrosis and apoptosis, and loss of cells integrity and function. Epigenetic regulation of gene expression is a growing research topic and is addressed by DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs express...

  13. Epigenetic changes in virus-associated human cancers

    Institute of Scientific and Technical Information of China (English)

    Hsin Pai LI; Yu Wei LEU; Yu Sun CHANG

    2005-01-01

    Epigenetics of human cancer becomes an area of emerging research direction due to a growing understanding of specific epigenetic pathways and rapid development of detection technologies. Aberrant promoter hypermethylation is a prevalent phenonmena in human cancers. Tumor suppressor genes are often hypermethylated due to the increased activity or deregulation of DNMTs. Increasing evidence also reveals that viral genes are one of the key players in regulating DNA methylation. In this review, we will focus on hypermethylation and tumor suppressor gene silencing and the signal pathways that are involved, particularly in cancers closely associated with the hepatitis B virus, simian virus 40 (SV40), and Epstein-Barr virus. In addition, we will discuss current technologies for genome-wide detection of epigenetically regulated targets, which allow for systematic DNA hypermethylation analysis. The study of epigenetic changes should provide a global view of gene profile in cancer, and epigenetic markers could be used for early detection,prognosis, and therapy of cancer.

  14. Epigenetics: heterochromatin meets RNAi

    Institute of Scientific and Technical Information of China (English)

    Ingela Djupedal; Karl Ekwall

    2009-01-01

    The term epigenetics refers to heritable changes not encoded by DNA. The organization of DNA into chromatin fibers affects gene expression in a heritable manner and is therefore one mechanism of epigenetic inheritance. Large parts of eukaryotic genomes consist of constitutively highly condensed heterochromatin, important for maintaining genome integrity but also for silencing of genes within. Small RNA, together with factors typically associated with RNA interference (RNAi) targets homologous DNA sequences and recruits factors that modify the chromatin, com-monly resulting in formation of heterochromatin and silencing of target genes. The scope of this review is to provide an overview of the roles of small RNA and the RNAi components, Dicer, Argonaute and RNA dependent polymeras-es in epigenetic inheritance via heterochromatin formation, exemplified with pathways from unicellular eukaryotes, plants and animals.

  15. 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.

  16. Epigenetic Therapy for Breast Cancer

    OpenAIRE

    Xiao-Yan Zhong; Feng-Feng Cai; Corina Kohler; Wei-Jie Chen; Bei Zhang; Ming-Hong Wang

    2011-01-01

    Both genetic and epigenetic alterations can control the progression of cancer. Genetic alterations are impossible to reverse, while epigenetic alterations are reversible. This advantage suggests that epigenetic modifications should be preferred in therapy applications. DNA methyltransferases and histone deacetylases have become the primary targets for studies in epigenetic therapy. Some DNA methylation inhibitors and histone deacetylation inhibitors are approved by the US Food and Drug Admini...

  17. Chromatographic elution profile of an analyte involved in reversible chemical reaction of the type A + B AB.

    Science.gov (United States)

    Kanatyeva, A Yu

    2007-05-25

    The chromatographic peak profile of the analyte involved in a chemical reaction of the type A + B AB is considered using method of the apparent adsorption isotherm. The apparent isotherms derived are nonlinear even under assumption of Henry isotherms of individual solutes. Nonlinearity of apparent adsorption isotherm results in peak distortion. The resulted chromatographic peak profile depends on several factors such as the equilibrium constant K(mob) and Henry constants of the solutes. Simulated peak profiles of solutes involved in the chemical reaction are presented as illustration of influence of various factors. PMID:16965781

  18. Cancer Development, Progression, and Therapy: An Epigenetic Overview

    Directory of Open Access Journals (Sweden)

    McKenna Longacre

    2013-10-01

    Full Text Available Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell–cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics.

  19. Epigenetic biomarkers in laboratory diagnostics: emerging approaches and opportunities.

    Science.gov (United States)

    Sandoval, Juan; Peiró-Chova, Lorena; Pallardó, Federico V; García-Giménez, José Luis

    2013-06-01

    Epigenetics has emerged as a new and promising field in recent years. Lifestyle, stress, drugs, physiopathological situations and pharmacological interventions have a great impact on the epigenetic code of the cells by altering the methylome, miRNA expression and the covalent histone modifications. Since there exists a need to find new biomarkers and improve diagnosis for several diseases, the research on epigenetic biomarkers for molecular diagnostics encourages the translation of this field from the bench to clinical practice. In this context, deciphering intricate epigenetic modifications involved in several molecular processes is a challenge that will be solved in the near future. In this review, the authors present an overview of the high-throughput technologies and laboratory techniques available for epigenetic studies, and also discuss which of them are more reliable to be used in a clinical diagnostic laboratory. In addition, the authors describe the most promising epigenetic biomarkers in lung, colorectal and prostate cancer, in which most advances have been achieved. Finally, the authors describe epigenetic biomarkers in some rare diseases; these rare syndromes are paradigms for a specific impaired molecular pathway, thus providing valuable information on the discovery of new epigenetic biomarkers. PMID:23782253

  20. Epigenetic Therapy in Lung Cancer

    OpenAIRE

    Liu, Stephen V.; Fabbri, Muller; Gitlitz, Barbara J.; Laird-Offringa, Ite A.

    2013-01-01

    Epigenetic deregulation 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.

  1. Importance of investigating epigenetic alterations for industry and regulators: An appraisal of current efforts by the Health and Environmental Sciences Institute

    International Nuclear Information System (INIS)

    Recent technological advances have led to rapid progress in the characterization of epigenetic modifications that control gene expression in a generally heritable way, and are likely involved in defining cellular phenotypes, developmental stages and disease status from one generation to the next. On November 18, 2013, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) held a symposium entitled “Advances in Assessing Adverse Epigenetic Effects of Drugs and Chemicals” in Washington, D.C. The goal of the symposium was to identify gaps in knowledge and highlight promising areas of progress that represent opportunities to utilize epigenomic profiling for risk assessment of drugs and chemicals. Epigenomic profiling has the potential to provide mechanistic information in toxicological safety assessments; this is especially relevant for the evaluation of carcinogenic or teratogenic potential and also for drugs that directly target epigenetic modifiers, like DNA methyltransferases or histone modifying enzymes. Furthermore, it can serve as an endpoint or marker for hazard characterization in chemical safety assessment. The assessment of epigenetic effects may also be approached with new model systems that could directly assess transgenerational effects or potentially sensitive stem cell populations. These would enhance the range of safety assessment tools for evaluating xenobiotics that perturb the epigenome. Here we provide a brief synopsis of the symposium, update findings since that time and then highlight potential directions for future collaborative efforts to incorporate epigenetic profiling into risk assessment

  2. Epigenetic mechanisms in neurological and neurodegenerative diseases.

    Directory of Open Access Journals (Sweden)

    Jorge eLandgrave-Gómez

    2015-02-01

    Full Text Available The role of epigenetic mechanisms in the function and homeostasis of the central nervous system (CNS and its regulation in diseases is one of the most interesting processes of contemporary neuroscience. In the last decade, a growing body of literature suggests that long-term changes in gene transcription associated with CNS´s regulation and neurological disorders are mediated via modulation of chromatin structure.Epigenetics, introduced for the first time by Waddington in the early 1940s, has been traditionally referred to a variety of mechanisms that allow heritable changes in gene expression even in the absence of DNA mutation. However, new definitions acknowledge that many of these mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons to control a variety of functions dependent on gene expression. Indeed, in the recent years these mechanisms have shown their importance in the maintenance of a healthy CNS. Moreover, environmental inputs that have shown effects in CNS diseases, such as nutrition, that can modulate the concentration of a variety of metabolites such as acetyl-coenzyme A (acetyl-coA, nicotinamide adenine dinucleotide (NAD+ and beta hydroxybutyrate (β-HB, regulates some of these epigenetic modifications, linking in a precise way environment with gene expression.This manuscript will portray what is currently understood about the role of epigenetic mechanisms in the function and homeostasis of the CNS and their participation in a variety of neurological disorders. We will discuss how the machinery that controls these modifications plays an important role in processes involved in neurological disorders such as neurogenesis and cell growth. Moreover, we will discuss how environmental inputs modulate these modifications producing metabolic and physiological alterations that could exert beneficial effects on neurological diseases. Finally, we will highlight possible future directions in the field of

  3. 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. PMID:26093659

  4. Overexpression of cancer-associated genes via epigenetic derepression mechanisms in gynecologic cancer

    Directory of Open Access Journals (Sweden)

    Hae MinJeong

    2014-02-01

    Full Text Available Like other cancers, most gynecologic cancers caused by aberrant expression of cancer-related genes. Epigenetics is one of important gene expression mechanisms which contribute to cancer development and progression by regulating cancer-related genes. Since the discovery of differential gene expression patterns in cancer cells compared with normal cells, extensive efforts have been made to explore the origins of abnormal gene expression in cancer. Epigenetics, the study inheritable changes in gene expression that do not alter DNA sequence, is a key area of this research. DNA methylation and histone modification are well-known epigenetic mechanisms, microRNAs and alternative splicing have recently been identified as important regulators of epigenetic changes. These epigenetic mechanisms not only affect specific target gene expression but also regulate the functioning of other epigenetic mechanisms. Moreover, these diverse epigenetic regulations occur simultaneously. Epigenetic regulation of gene expression is extraordinarily complicated and requires that all epigenetic mechanisms be studied at once to determine the exact gene regulation mechanisms. Traditionally, the contribution of epigenetics to cancer is thought to be mediated through the inactivation of tumor suppressor genes (TSGs expression. But recently it is arising that some oncogenes or cancer-promoting genes (CPGs are overexpressed in diverse type of cancers through epigenetic derepression mechanism, such as DNA demethylation, histone demethylation. Epigenetic derepression arises from diverse epigenetic changes, and all of these mechanisms are actively interact each other to increase oncogenes or CPGs expression in cancer cell. Oncogenes or CPGs overexpressed through epigenetic derepression can initiate cancer development, and the accumulation of these abnormal epigenetic changes makes cancer more aggressive and resistant to treatment. This review discusses epigenetic mechanisms involved

  5. Epigenetics and Future Generations.

    Science.gov (United States)

    Del Savio, Lorenzo; Loi, Michele; Stupka, Elia

    2015-10-01

    Recent evidence of intergenerational epigenetic programming of disease risk broadens the scope of public health preventive interventions to future generations, i.e. non existing people. Due to the transmission of epigenetic predispositions, lifestyles such as smoking or unhealthy diet might affect the health of populations across several generations. While public policy for the health of future generations can be justified through impersonal considerations, such as maximizing aggregate well-being, in this article we explore whether there are rights-based obligations supervening on intergenerational epigenetic programming despite the non-identity argument, which challenges this rationale in case of policies that affect the number and identity of future people. We propose that rights based obligations grounded in the interests of non-existing people might fall upon existing people when generations overlap. In particular, if environmental exposure in F0 (i.e. existing people) will affect the health of F2 (i.e. non-existing people) through epigenetic programming, then F1 (i.e. existing and overlapping with both F0 and F2) might face increased costs to address F2's condition in the future: this might generate obligations upon F0 from various distributive principles, such as the principle of equal opportunity for well being. PMID:25644664

  6. Study of the Chemical Mechanism Involved in the Formation of Tungstite in Benzyl Alcohol by the Advanced QEXAFS Technique

    DEFF Research Database (Denmark)

    Olliges‐Stadler, Inga; Stötzel, Jan; Koziej, Dorota;

    2012-01-01

    Insight into the complex chemical mechanism for the formation of tungstite nanoparticles obtained by the reaction of tungsten hexachloride with benzyl alcohol is presented herein. The organic and inorganic species involved in the formation of the nanoparticles were studied by time‐dependent gas c...

  7. Epigenetic biomarkers in prostate cancer: Current and future uses.

    Science.gov (United States)

    Chiam, Karen; Ricciardelli, Carmela; Bianco-Miotto, Tina

    2014-01-28

    Epigenome alterations are characteristic of nearly all human malignancies and include changes in DNA methylation, histone modifications and microRNAs (miRNAs). However, what induces these epigenetic alterations in cancer is largely unknown and their mechanistic role in prostate tumorigenesis is just beginning to be evaluated. Identification of the epigenetic modifications involved in the development and progression of prostate cancer will not only identify novel therapeutic targets but also prognostic and diagnostic markers. This review will focus on the use of epigenetic modifications as biomarkers for prostate cancer. PMID:22391123

  8. Toxicological Mechanism of Endocrine Disrupting Chemicals:Is Estrogen Receptor Involved?

    OpenAIRE

    Jeung, Eui-Bae; Choi, Kyung-Chul

    2010-01-01

    Endocrine disrupting chemicals (EDCs) have been shown to interfere with physiological systems, i.e., adversely affecting hormone balance (endocrine system) , or disrupting normal function, in the female and male reproductive organs. Although endocrine disruption is a global concern for human health, its impact and significance and the screening strategy for detecting these synthetic or man-made chemicals are not clearly understood in female and male reproductive functions. Thus, in this revie...

  9. [Epigenetics: a novel tool for early diagnosis and tumor therapy].

    Science.gov (United States)

    Filetici, Patrizia

    2015-01-01

    Epigenetics, first described by Conrad Waddington, defines how pathways setting a specific phenotype and heritable cellular functions are activated in a DNA independent way. Epigenetics concerns the study of genome structure and accessibility that regulates patterns of gene expression through the dynamic compaction and opening the chromatin structure. Vincent Allfrey profetically declared in 1964 that histone modifications could influence gene expression. In cancer very often cells show a profound modification of DNA methylation and mutations in chromatin regulators. These evidences provided therefore a clear link between epigenetics and neoplasia. Advanced molecular technology such as Deep-sequencing and ChIP-Seq revealed the frequent relocalization in cancer of many PTM readers such the Ac-Lys binding bromodomain. These results were important for the development of novel classes of epigenetic drugs some of which are inhibitors of histone modifyers or molecule interacting with reader domains. Since cancer imply profound changes in the epigenetic profile and in gene transcription a future challenge of molecular and chemical biology will be to develop novel epigenetic compounds able to correct the epigenetic disfunction and, possibly, coadiuvate canonical therapy in the cure of cancer. PMID:25621778

  10. The Mendelian disorders of the epigenetic machinery.

    Science.gov (United States)

    Bjornsson, Hans Tomas

    2015-10-01

    The Mendelian disorders of the epigenetic machinery are genetic disorders that involve disruption of the various components of the epigenetic machinery (writers, erasers, readers, and remodelers) and are thus expected to have widespread downstream epigenetic consequences. Studying this group may offer a unique opportunity to learn about the role of epigenetics in health and disease. Among these patients, neurological dysfunction and, in particular, intellectual disability appears to be a common phenotype; however, this is often seen in association with other more specific features in respective disorders. The specificity of some of the clinical features raises the question whether specific cell types are particularly sensitive to the loss of these factors. Most of these disorders demonstrate dosage sensitivity as loss of a single allele appears to be sufficient to cause the observed phenotypes. Although the pathogenic sequence is unknown for most of these disorders, there are several examples where disrupted expression of downstream target genes accounts for a substantial portion of the phenotype; hence, it may be useful to systematically map such disease-relevant target genes. Finally, two of these disorders (Rubinstein-Taybi and Kabuki syndromes) have shown post-natal rescue of markers of the neurological dysfunction with drugs that lead to histone deacetylase inhibition, indicating that some of these disorders may be treatable causes of intellectual disability. PMID:26430157

  11. 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.

  12. Principles of epigenetic inheritance

    Czech Academy of Sciences Publication Activity Database

    Vyskot, Boris

    České Budějovice, 2008. s. 11-13. ISBN 80-85645-59-9. [XXIII Genetic Days. 10.09.2008-12.09.2008, České Budějovice] R&D Projects: GA MŠk(CZ) LC06004; GA ČR(CZ) GA521/06/0056 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : epigenetics * inheritance * gene Subject RIV: BO - Biophysics

  13. Genetic syndromes caused by mutations in epigenetic genes.

    Science.gov (United States)

    Berdasco, María; Esteller, Manel

    2013-04-01

    The orchestrated organization of epigenetic factors that control chromatin dynamism, including DNA methylation, histone marks, non-coding RNAs (ncRNAs) and chromatin-remodeling proteins, is essential for the proper function of tissue homeostasis, cell identity and development. Indeed, deregulation of epigenetic profiles has been described in several human pathologies, including complex diseases (such as cancer, cardiovascular and neurological diseases), metabolic pathologies (type 2 diabetes and obesity) and imprinting disorders. Over the last decade it has become increasingly clear that mutations of genes involved in epigenetic mechanism, such as DNA methyltransferases, methyl-binding domain proteins, histone deacetylases, histone methylases and members of the SWI/SNF family of chromatin remodelers are linked to human disorders, including Immunodeficiency Centromeric instability Facial syndrome 1, Rett syndrome, Rubinstein-Taybi syndrome, Sotos syndrome or alpha-thalassemia/mental retardation X-linked syndrome, among others. As new members of the epigenetic machinery are described, the number of human syndromes associated with epigenetic alterations increases. As recent examples, mutations of histone demethylases and members of the non-coding RNA machinery have recently been associated with Kabuki syndrome, Claes-Jensen X-linked mental retardation syndrome and Goiter syndrome. In this review, we describe the variety of germline mutations of epigenetic modifiers that are known to be associated with human disorders, and discuss the therapeutic potential of epigenetic drugs as palliative care strategies in the treatment of such disorders. PMID:23370504

  14. Sperm is epigenetically programmed to regulate gene transcription in embryos.

    Science.gov (United States)

    Teperek, Marta; Simeone, Angela; Gaggioli, Vincent; Miyamoto, Kei; Allen, George E; Erkek, Serap; Kwon, Taejoon; Marcotte, Edward M; Zegerman, Philip; Bradshaw, Charles R; Peters, Antoine H F M; Gurdon, John B; Jullien, Jerome

    2016-08-01

    For a long time, it has been assumed that the only role of sperm at fertilization is to introduce the male genome into the egg. Recently, ideas have emerged that the epigenetic state of the sperm nucleus could influence transcription in the embryo. However, conflicting reports have challenged the existence of epigenetic marks on sperm genes, and there are no functional tests supporting the role of sperm epigenetic marking on embryonic gene expression. Here, we show that sperm is epigenetically programmed to regulate embryonic gene expression. By comparing the development of sperm- and spermatid-derived frog embryos, we show that the programming of sperm for successful development relates to its ability to regulate transcription of a set of developmentally important genes. During spermatid maturation into sperm, these genes lose H3K4me2/3 and retain H3K27me3 marks. Experimental removal of these epigenetic marks at fertilization de-regulates gene expression in the resulting embryos in a paternal chromatin-dependent manner. This demonstrates that epigenetic instructions delivered by the sperm at fertilization are required for correct regulation of gene expression in the future embryos. The epigenetic mechanisms of developmental programming revealed here are likely to relate to the mechanisms involved in transgenerational transmission of acquired traits. Understanding how parental experience can influence development of the progeny has broad potential for improving human health. PMID:27034506

  15. Environmentally induced epigenetic toxicity: potential public health concerns.

    Science.gov (United States)

    Marczylo, Emma L; Jacobs, Miriam N; Gant, Timothy W

    2016-09-01

    Throughout our lives, epigenetic processes shape our development and enable us to adapt to a constantly changing environment. Identifying and understanding environmentally induced epigenetic change(s) that may lead to adverse outcomes is vital for protecting public health. This review, therefore, examines the present understanding of epigenetic mechanisms involved in the mammalian life cycle, evaluates the current evidence for environmentally induced epigenetic toxicity in human cohorts and rodent models and highlights the research considerations and implications of this emerging knowledge for public health and regulatory toxicology. Many hundreds of studies have investigated such toxicity, yet relatively few have demonstrated a mechanistic association among specific environmental exposures, epigenetic changes and adverse health outcomes in human epidemiological cohorts and/or rodent models. While this small body of evidence is largely composed of exploratory in vivo high-dose range studies, it does set a precedent for the existence of environmentally induced epigenetic toxicity. Consequently, there is worldwide recognition of this phenomenon, and discussion on how to both guide further scientific research towards a greater mechanistic understanding of environmentally induced epigenetic toxicity in humans, and translate relevant research outcomes into appropriate regulatory policies for effective public health protection. PMID:27278298

  16. Neurogenesis-based epigenetic therapeutics for Alzheimer's disease (Review).

    Science.gov (United States)

    Li, Xueyuan; Bao, Xinjie; Wang, Renzhi

    2016-08-01

    Alzheimer's disease (AD) is a worldwide health problem with multiple pathogenic causes including aging, and genetic and environmental factors. As the interfaces between genes and the environment, epigenetic mechanisms, including DNA methylation, histone modification and microRNAs, are also involved in the pathogenesis of AD. Neurogenesis occurs throughout life in the normal adult brain of mammals. The neurogenic process, consisting of the proliferation, differentiation and maturation of neural stem cells (NSC), is regulated via epigenetic mechanisms by controlling the expression of specific sets of genes. In the pathology of AD, due to impairments in epigenetic mechanisms, the generation of neurons from NSCs is damaged, which exacerbates the loss of neurons and the deficits in learning and memory function associated with AD. Based on neurogenesis, a number of therapeutic strategies have shown capability in promoting neuronal generation to compensate for the neurons lost in AD, thereby improving cognitive function through epigenetic modifications. This provides potential for the treatment of AD by stimulating neurogenesis using epigenetic strategies. The present review discusses the epigenetics of AD and adult neurogenesis, and summarizes the neurogenesis-based epigenetic therapies targeted at AD. Such a review may offer information for the guidance of future developments of therapeutic strategies for AD. PMID:27314984

  17. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression.

    Science.gov (United States)

    Feinberg, Andrew P; Koldobskiy, Michael A; Göndör, Anita

    2016-05-01

    This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of 'tumour progenitor genes'. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: 'epigenetic mediators', corresponding to the tumour progenitor genes suggested earlier; 'epigenetic modifiers' of the mediators, which are frequently mutated in cancer; and 'epigenetic modulators' upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer. PMID:26972587

  18. Chemical -induced apoptotic cell death in tomato cells : involvement of caspase-like proteases

    NARCIS (Netherlands)

    Jong, de A.J.; Hoeberichts, F.A.; Yakimova, E.T.; Maximova, E.; Woltering, E.J.

    2000-01-01

    A new system to study programmed cell death in plants is described. Tomato (Lycopersicon esculentum Mill.) suspension cells were induced to undergo programmed cell death by treatment with known inducers of apoptosis in mammalian cells. This chemical-induced cell death was accompanied by the characte

  19. The chemical stockpile intergovernmental consultation program: Lessons for HLW public involvement

    International Nuclear Information System (INIS)

    This paper assesses the appropriateness of the US Army's Chemical Stockpile Disposal Program's (CSDP) Intergovernmental Consultation and Coordination Boards (ICCBs) as models for incorporating public concerns in the future siting of HLW repositories by DOE. ICCB structure, function, and implementation are examined, along with other issues relevant to the HLW context. 27 refs

  20. Current issues involving screening and identification of chemical contaminants in foods by mass spectrometry

    Science.gov (United States)

    Although quantitative analytical methods must be empirically validated prior to their actual use in a variety of applications, including regulatory monitoring of chemical adulterants in foods, validation of qualitative method performance for the analytes and matrices of interest is frequently ignore...

  1. Current issues involving screening and identification of chemical contaminants in foods by mass spectrometry

    NARCIS (Netherlands)

    Lehotay, S.J.; Sapozhnikova, Y.; Mol, J.G.J.

    2015-01-01

    Although quantitative analytical methods must be empirically validated prior to their use in a variety of applications, including regulatory monitoring of chemical adulterants in foods, validation of qualitative method performance for the analytes and matrices of interest is frequently ignored, or g

  2. Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease.

    Science.gov (United States)

    Nicolia, Vincenzina; Lucarelli, Marco; Fuso, Andrea

    2015-08-01

    Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. Therefore, it is easy to understand why recent literature focuses on the epigenetic modifications associated with Alzheimer's disease and other neurodegenerative disorders. One of the most intriguing and, at the same time, worrying evidence is that even "mild" environmental factors (such as behavioral or physical stress) as well as the under-threshold exposure to pollutants and chemicals, can be effective. Finally, even mild nutrients disequilibria can result in long-lasting and functional alterations of many epigenetic markers, although they don't have an immediate acute effect. Therefore, we will probably have to re-define the current risk threshold for many factors, molecules and stresses. Among the many different environmental factors affecting the epigenome, nutrition represents one of the most investigated fields; the reasons are probably that each person interacts with nutrients and that, in turn, nutrients can modulate at molecular level the epigenetic biochemical pathways. The role that nutrition can exert in modulating epigenetic modifications in Alzheimer's disease will be discussed with particular emphasis on the role of B vitamins and DNA methylation. PMID:25456841

  3. Epigenetic transmission of Holocaust trauma: can nightmares be inherited?

    Science.gov (United States)

    Kellermann, Natan Pf

    2013-01-01

    The Holocaust left its visible and invisible marks not only on the survivors, but also on their children. Instead of numbers tattooed on their forearms, however, they may have been marked epigenetically with a chemical coating upon their chromosomes, which would represent a kind of biological memory of what the parents experienced. as a result, some suffer from a general vulnerability to stress while others are more resilient. Previous research assumed that such transmission was caused by environmental factors, such as the parents' childrearing behavior. New research, however, indicates that these transgenerational effects may have been also (epi) genetically transmitted to their children. Integrating both hereditary and environmental factors, epigenetics adds a new and more comprehensive psychobiological dimension to the explanation of transgenerational transmission of trauma. Specifically, epigenetics may explain why latent transmission becomes manifest under stress. a general theoretical overview of epigenetics and its relevance to research on trauma transmission is presented. PMID:24029109

  4. Epigenetic advances in clinical neuroscience

    OpenAIRE

    Abel, Ted; Poplawski, Shane

    2014-01-01

    Epigenetics, broadly defined as the regulation of gene expression without alteration of the genome, has become a field of tremendous interest in neuroscience, neurology, and psychiatry. This research has rapidly changed the way researchers think about brain function. Exciting epigenetic discoveries have been found in addiction, early life stress, neurodegeneration, post-traumatic stress disorder, and depression. As researchers more precisely define the epigenetic landscape that regulates dise...

  5. Epigenetics: What it is about?

    Directory of Open Access Journals (Sweden)

    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.

  6. An operational definition of epigenetics

    OpenAIRE

    Berger, Shelley L.; Kouzarides, Tony; Shiekhattar, Ramin; Shilatifard, Ali

    2009-01-01

    A recent meeting (December 2008) regarding chromatin-based epigenetics was hosted by the Banbury Conference Center and Cold Spring Harbor Laboratory. The intent was to discuss aspects of epigenetic control of genomic function, and to arrive at a consensus definition of “epigenetics” to be considered by the broader community. It was evident that multiple mechanistic steps lead to the stable heritance of the epigenetic phenotype. Below we provide our view and interpretation of the proceedings a...

  7. Tabulation of thermodynamic data for chemical reactions involving 58 elements common to radioactive waste package systems

    International Nuclear Information System (INIS)

    The rate of release and migration of radionuclides from a nuclear waste repository to the biosphere is dependent on chemical interactions between groundwater, the geologic host rock, and the radioactive waste package. For the purpose of this report, the waste package includes the wasteform, canister, overpack, and repository backfill. Chemical processes of interest include sorption (ion exchange), dissolution, complexation, and precipitation. Thermochemical data for complexation and precipitation calculations for 58 elements common to the radioactive waste package are presented. Standard free energies of formation of free ions, complexes, and solids are listed. Common logarithms of equilibrium constants (log K's) for speciation and precipitation reactions are listed. Unless noted otherwise, all data are for 298.150K and one atmosphere

  8. Divergent evolution of CHD3 proteins resulted in MOM1 refining epigenetic control in vascular plants

    OpenAIRE

    Marian Caikovski; Chotika Yokthongwattana; Yoshiki Habu; Taisuke Nishimura; Olivier Mathieu; Jerzy Paszkowski

    2008-01-01

    Author Summary Epigenetic regulation of transcription usually involves changes in histone modifications, as well as DNA methylation changes in plants and mammals. Previously, we found an exceptional epigenetic regulator in Arabidopsis, MOM1, acting independently of these epigenetic marks. Interestingly, MOM1 controls loci associated with bivalent chromatin marks, intermediate to active euchromatin and silent heterochromatin. Such bivalent marks are often associated with newly inserted and/or ...

  9. Chemical reactions involved in the initiation of hot corrosion of IN-738

    Science.gov (United States)

    Fryburg, G. C.; Kohl, F. J.; Stearns, C. A.

    1984-01-01

    Sodium-sulfate-induced hot corrosion of preoxidized IN-738 was studied at 975 C with special emphasis placed on the processes occurring during the long induction period. Thermogravimetric tests were run for predetermined periods of time, and then one set of specimens was washed with water. Chemical analysis of the wash solutions yielded information about water soluble metal salts and residual sulfate. A second set of samples was cross sectioned dry and polished in a nonaqueous medium. Element distributions within the oxide scale were obtained from electron microprobe X-ray micrographs. Evolution of SO was monitored throughout the thermogravimetric tests. Kinetic rate studies were performed for several pertinent processes; appropriate rate constants were obtained from the following chemical reactions; Cr203 + 2 Na2S04(1) + 3/2 02 yields 2 Na2Cr04(1) + 2 S03(g)n TiO2 + Na2S04(1) yields Na20(T102)n + 503(g)n T102 + Na2Cro4(1) yields Na2(T102)n + Cr03(g).

  10. Nucleosome Positioning and Epigenetics

    Science.gov (United States)

    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.

  11. Epigenetics of the yeast galactose genetic switch

    Indian Academy of Sciences (India)

    Paike Jayadeva Bhat; Revathi S Iyer

    2009-10-01

    The transcriptional activation of enzymes involved in galactose utilization (GAL genes) in Saccharomyces cerevisiae is regulated by a complex interplay between three regulatory proteins encoded by GAL4 (transcriptional activator), GAL3 (signal transducer) and GAL80 (repressor). The relative concentrations of the signal transducer and the repressor are maintained by autoregulation. Cells disabled for autoregulation exhibit phenotypes distinctly different from that of the wild type cells, enabling us to explore the biological significance of autoregulation. The redundancy in signal transduction due to the presence of GAL1 (alternate signal transducer) also makes it a suitable model to understand the phenomenon of epigenetics. In this article we review some of the recent attempts made to understand the importance of epigenetics in the establishment of cellular and transcriptional memory.

  12. A simple histone code opens many paths to epigenetics.

    Science.gov (United States)

    Sneppen, Kim; Dodd, Ian B

    2012-01-01

    Nucleosomes can be covalently modified by addition of various chemical groups on several of their exposed histone amino acids. These modifications are added and removed by enzymes (writers) and can be recognized by nucleosome-binding proteins (readers). Linking a reader domain and a writer domain that recognize and create the same modification state should allow nucleosomes in a particular modification state to recruit enzymes that create that modification state on nearby nucleosomes. This positive feedback has the potential to provide the alternative stable and heritable states required for epigenetic memory. However, analysis of simple histone codes involving interconversions between only two or three types of modified nucleosomes has revealed only a few circuit designs that allow heritable bistability. Here we show by computer simulations that a histone code involving alternative modifications at two histone positions, producing four modification states, combined with reader-writer proteins able to distinguish these states, allows for hundreds of different circuits capable of heritable bistability. These expanded possibilities result from multiple ways of generating two-step cooperativity in the positive feedback--through alternative pathways and an additional, novel cooperativity motif. Our analysis reveals other properties of such epigenetic circuits. They are most robust when the dominant nucleosome types are different at both modification positions and are not the type inserted after DNA replication. The dominant nucleosome types often recruit enzymes that create their own type or destroy the opposing type, but never catalyze their own destruction. The circuits appear to be evolutionary accessible; most circuits can be changed stepwise into almost any other circuit without losing heritable bistability. Thus, our analysis indicates that systems that utilize an expanded histone code have huge potential for generating stable and heritable nucleosome

  13. A simple histone code opens many paths to epigenetics.

    Directory of Open Access Journals (Sweden)

    Kim Sneppen

    Full Text Available Nucleosomes can be covalently modified by addition of various chemical groups on several of their exposed histone amino acids. These modifications are added and removed by enzymes (writers and can be recognized by nucleosome-binding proteins (readers. Linking a reader domain and a writer domain that recognize and create the same modification state should allow nucleosomes in a particular modification state to recruit enzymes that create that modification state on nearby nucleosomes. This positive feedback has the potential to provide the alternative stable and heritable states required for epigenetic memory. However, analysis of simple histone codes involving interconversions between only two or three types of modified nucleosomes has revealed only a few circuit designs that allow heritable bistability. Here we show by computer simulations that a histone code involving alternative modifications at two histone positions, producing four modification states, combined with reader-writer proteins able to distinguish these states, allows for hundreds of different circuits capable of heritable bistability. These expanded possibilities result from multiple ways of generating two-step cooperativity in the positive feedback--through alternative pathways and an additional, novel cooperativity motif. Our analysis reveals other properties of such epigenetic circuits. They are most robust when the dominant nucleosome types are different at both modification positions and are not the type inserted after DNA replication. The dominant nucleosome types often recruit enzymes that create their own type or destroy the opposing type, but never catalyze their own destruction. The circuits appear to be evolutionary accessible; most circuits can be changed stepwise into almost any other circuit without losing heritable bistability. Thus, our analysis indicates that systems that utilize an expanded histone code have huge potential for generating stable and heritable

  14. Epigenetics & chromatin: Interactions and processes

    NARCIS (Netherlands)

    S. Henikoff (Steven); F.G. Grosveld (Frank)

    2013-01-01

    textabstractOn 11 to 13 March 2013, BioMed Central will be hosting its inaugural conference, Epigenetics & Chromatin: Interactions and Processes, at Harvard Medical School, Cambridge, MA, USA. Epigenetics & Chromatin has now launched a special article series based on the general themes of the confer

  15. Is Glioblastoma an Epigenetic Malignancy?

    International Nuclear Information System (INIS)

    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

  16. Is Glioblastoma an Epigenetic Malignancy?

    Energy Technology Data Exchange (ETDEWEB)

    Maleszewska, Marta; Kaminska, Bozena, E-mail: B.Kaminska@nencki.gov.pl [Laboratory of Molecular Neurobiology, Neurobiology Center, The Nencki Institute of Experimental Biology, 3 Pasteur Str., Warsaw 02-093 (Poland)

    2013-09-03

    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.

  17. PHYSIC AND CHEMICAL BASIS FOR THE INVOLVEMENT OF D-ELEMENTS OF THE FOURTH GROUP (TITANIUM, ZIRCONIUM, HAFNIUM) IN THE SYNTHESIS OF BUILDING AND SILICATE MATERIALS

    OpenAIRE

    BOLSHAKOV V. I.; Savin, Yu. L.; O. P. Prykhodko; L. S. Savin; Kulbashnyi, V. M.

    2007-01-01

    In the paper the studies of physico-chemical grounds of involving the fourth group elements (titanium, zirconium, hafnium) for syntheses of construction silicate materials are presented. The physico-chemical approach proposed allows involving the great group of technogenic titanium-containing semi-products, concentrates, slags and slimes for production of construction silicate materials and manufacture the products and building structures.

  18. PHYSIC AND CHEMICAL BASIS FOR THE INVOLVEMENT OF D-ELEMENTS OF THE FOURTH GROUP (TITANIUM, ZIRCONIUM, HAFNIUM) IN THE SYNTHESIS OF BUILDING AND SILICATE MATERIALS

    OpenAIRE

    BOLSHAKOV V. I.; Savin, Yu. L.; O. P. Prykhodko; L. S. Savin; Kulbashnyi, V. M.

    2008-01-01

    In the paper the studies of physico-chemical grounds of involving the fourth group elements (titanium, zirconium, hafnium) for syntheses of construction silicate materials are presented. The physico-chemical approach proposed allows involving the great group of technogenic titanium-containing semi-products, concentrates, slags and slimes for production of construction silicate materials and manufacture the products and building structures.

  19. Using an Active-Learning Approach to Teach Epigenetics

    Science.gov (United States)

    Colon-Berlingeri, Migdalisel

    2010-01-01

    Epigenetics involves heritable changes in gene expression that do not involve alterations in the DNA sequence. I developed an active-learning approach to convey this topic to students in a college genetics course. I posted a brief summary of the topic before class to stimulate exchange in cooperative groups. During class, we discussed the…

  20. The changing concept of epigenetics.

    Science.gov (United States)

    Jablonka, Eva; Lamb, Marion J

    2002-12-01

    We discuss the changing use of epigenetics, a term coined by Conrad Waddington in the 1940s, and how the epigenetic approach to development differs from the genetic approach. Originally, epigenetics referred to the study of the way genes and their products bring the phenotype into being. Today, it is primarily concerned with the mechanisms through which cells become committed to a particular form or function and through which that functional or structural state is then transmitted in cell lineages. We argue that modern epigenetics is important not only because it has practical significance for medicine, agriculture, and species conservation, but also because it has implications for the way in which we should view heredity and evolution. In particular, recognizing that there are epigenetic inheritance systems through which non-DNA variations can be transmitted in cell and organismal lineages broadens the concept of heredity and challenges the widely accepted gene-centered neo-Darwinian version of Darwinism. PMID:12547675

  1. Photo- and radiation chemical studies of intermediates involved in excited-state electron-transfer reactions

    International Nuclear Information System (INIS)

    Excited-state inter- and intramolecular electron-transfer reactions lie at the heart of the most photochemical solar energy conversion schemes. The authors research, which has utilized the techniques of continuous and pulsed photolysis and radiolysis, has focused on three general aspects of these reactions involving transition metal coordination complexes and electron donor-acceptor complexes: i) the effect of solution medium on the properties and quenching of the excited states; ii) the control of the quantum yields of formation of redox products; iii) the mechanism by which reduced species interact with water to yield H2 homogeneously and heterogeneously. EDTA is among the most popular sacrificial electron donors used in model systems. Its role is to scavenge the oxidized form of the photosensitizer in order to prevent its rapid reaction with the reduced form of the electron relay species that results from the electron-transfer quenching of the excited photosensitizer. In systems involving MV2+, the radicals resulting from the oxidation of EDTA can eventually lead to the generation of a second equivalent of MV+; the reducing agent is believed to be a radical localized on the carbon atom alpha to the carboxylate group. The reaction of radiolytically-generated OH/H with EDTA produces this radical directly via H-abstraction or indirectly via deprotonation of the carbon atom adjacent to the nitrogen radical site in the oxidized amine moiety; it reduces MV2+ with rate constants of 2.8 x 109, 7.6 x 109, and 8.5 x 106M-1s-1 at pH 12.5, 8.3, and 4.7, respectively. Degradative decarboxylation of EDTA-radicals and their back electron-transfer reactions are enhanced in acidic solution causing the yield of MV+ to be severely diminished

  2. Study of chemical processes involved in silver staining of gold nanostructures by Raman scattering

    Science.gov (United States)

    Ji, Xiaohui; Yang, Wensheng

    2016-05-01

    Strong Raman enhancement contributed by ``hot spots'' in directly fused gold dimers offer a selective and sensitive tool for understanding the surface processes involved in the silver staining of gold nanostructures. These processes include the interactions of cations, effects of surface adsorbed Cl- ions, surface replacement of ligands, and reduction of silver ions on the surface of the gold nanocrystals. Results show that in the commonly applied silver staining scheme for gold nanostructures, i.e., the addition of the Raman probe after the deposition of the silver shell, the Raman signals of the probe (p-mercaptobenzoic acid) were weakened greatly, due to the pre-existence of the Cl--Ag+-citrate bridges on the surface of the gold. A new scheme was developed for silver deposition after pre-adsorption of the probe, which achieved a Raman enhancement factor as high as ~5 × 108.Strong Raman enhancement contributed by ``hot spots'' in directly fused gold dimers offer a selective and sensitive tool for understanding the surface processes involved in the silver staining of gold nanostructures. These processes include the interactions of cations, effects of surface adsorbed Cl- ions, surface replacement of ligands, and reduction of silver ions on the surface of the gold nanocrystals. Results show that in the commonly applied silver staining scheme for gold nanostructures, i.e., the addition of the Raman probe after the deposition of the silver shell, the Raman signals of the probe (p-mercaptobenzoic acid) were weakened greatly, due to the pre-existence of the Cl--Ag+-citrate bridges on the surface of the gold. A new scheme was developed for silver deposition after pre-adsorption of the probe, which achieved a Raman enhancement factor as high as ~5 × 108. Electronic supplementary information (ESI) available: Fig. S1-S3. See DOI: 10.1039/c6nr01208f

  3. Epigenetics: A possible answer to the undeciphered etiopathogenesis and behavior of oral lesions.

    Science.gov (United States)

    Singh, Narendra Nath; Peer, Aakanksha; Nair, Sherin; Chaturvedi, Rupesh K

    2016-01-01

    Much controversy has existed over the etiopathogenesis and management of oral lesions, especially oral malignancies. The knowledge of genetic basis is proving to be inadequate in the light of emerging new mechanisms termed epigenetic phenomena. The present review article aims to understand the role of epigenetic mechanisms in oral lesions. Epigenetics is the study of acquired changes in chromatin structure that arise independently of a change in the underlying deoxyribonucleic acid (DNA) nucleotide sequence. Key components involved in epigenetic regulation are DNA methylation, histone modifications and modifications in micro ribonucleic acids (miRNA). Epigenetics is a reversible system that can be affected by various environmental factors such as diet, drugs, mental stress, physical activity and addictive substances such as tobacco, nicotine and alcohol. Epigenetics may also play a role in explaining the etiopathogenesis of developmental anomalies, genetic defects, cancer as well as substance addiction (tobacco, cigarette and alcohol). Epigenetic modifications may contribute to aberrant epigenetic mechanisms seen in oral precancers and cancers. In the near future, epigenetic variations found in oral dysplastic cells can act as a molecular fingerprint for malignancies. The literature in English language was searched and a structured scientific review and meta-analysis of scientific publications from the year 2000 to year 2015 was carried out from various journals. It was observed that epigenetic marks can prove to be novel markers for early diagnosis, prognosis and treatment of oral cancers as well as other oral diseases. PMID:27194874

  4. Economic Evaluations for the Carbon Dioxide-involved Production of High-value Chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ji Hyun; Lee, Dong Woog; Jang, Se Gyu; Kwak, No-Sang; Lee, In Young; Jang, Kyung Ryoung; Shim, Jae-Goo [KEPCO Research Institute, Daejon (Korea, Republic of); Choi, Jong Shin [Korea East-West Power Co. LTD, Seoul (Korea, Republic of)

    2014-06-15

    Economic evaluation of the manufacturing technology of high-value chemicals through the carbonation reaction of carbon dioxide contained in the flue gas was performed, and analysis of the IRR (Internal Rate of Return) and whole profit along the production plan of the final product was conducted. Through a carbonation reaction with sodium hydroxide that is generated from electrolysis and by using carbon dioxide in the combustion gas that is generated in the power plant, it is possible to get a high value products such as sodium bicarbonate compound and also to reduce the carbon dioxide emission simultaneously. The IRR (Internal Rate of Return) and NPV (Net Present Value) methods were used for the economic evaluation of the process which could handle carbon dioxide of 100 tons per day in the period of the 20 years of plant operation. The results of economic evaluation showed that the IRR of baseline case of technology was 67.2% and the profit that obtained during the whole operation period (20 years) was 346,922 million won based on NPV value. When considering ETS due to the emissions trading enforcement that will be activated in 2015, the NPV was improved to a 6,000 million won. Based on this results, it could be concluded that this CO2 carbonation technology is an cost-effective technology option for the reduction of greenhouse gas.

  5. Economic Evaluations for the Carbon Dioxide-involved Production of High-value Chemicals

    International Nuclear Information System (INIS)

    Economic evaluation of the manufacturing technology of high-value chemicals through the carbonation reaction of carbon dioxide contained in the flue gas was performed, and analysis of the IRR (Internal Rate of Return) and whole profit along the production plan of the final product was conducted. Through a carbonation reaction with sodium hydroxide that is generated from electrolysis and by using carbon dioxide in the combustion gas that is generated in the power plant, it is possible to get a high value products such as sodium bicarbonate compound and also to reduce the carbon dioxide emission simultaneously. The IRR (Internal Rate of Return) and NPV (Net Present Value) methods were used for the economic evaluation of the process which could handle carbon dioxide of 100 tons per day in the period of the 20 years of plant operation. The results of economic evaluation showed that the IRR of baseline case of technology was 67.2% and the profit that obtained during the whole operation period (20 years) was 346,922 million won based on NPV value. When considering ETS due to the emissions trading enforcement that will be activated in 2015, the NPV was improved to a 6,000 million won. Based on this results, it could be concluded that this CO2 carbonation technology is an cost-effective technology option for the reduction of greenhouse gas

  6. Involvement of Subcortical Brain Structures During Olfactory Stimulation in Multiple Chemical Sensitivity.

    Science.gov (United States)

    Alessandrini, Marco; Micarelli, Alessandro; Chiaravalloti, Agostino; Bruno, Ernesto; Danieli, Roberta; Pierantozzi, Mariangela; Genovesi, Giuseppe; Öberg, Johanna; Pagani, Marco; Schillaci, Orazio

    2016-03-01

    Multiple chemical sensitivity (MCS) patients usually react to odour compounds and the majority of neuroimaging studies assessed, especially at the cortical level, many olfactory-related correlates. The purpose of the present study was to depict sub-cortical metabolic changes during a neutral (NC) and pure (OC) olfactory stimulation by using a recently validated (18)F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computer tomography procedure in 26 MCS and 11 healthy (HC) resting subjects undergoing a battery of clinical tests. Twelve subcortical volumes of interest were identified by the automated anatomical labeling library and normalized to thalamus FDG uptake. In both groups, when comparing OC to NC, the within-subjects ANOVA demonstrated a relative decreased metabolism in bilateral putamen and hippocampus and a relative increased metabolism in bilateral amygdala, olfactory cortex (OLF), caudate and pallidum. The between-groups ANOVA demonstrated in MCS a significant higher metabolism in bilateral OLF during NC. As in HC subjects negative correlations were found in OC between FDG uptake in bilateral amygdala and hippocampus and odor pleasantness scale, the latter positively correlated with MCS subjects' bilateral putamen FDG uptake in OC. Besides FDG uptake resemblances in both groups were found, for the first time a relative higher metabolism increase in OLF in MCS subjects at rest with respect to HC was found. When merging this aspect to the different subcortical FDG uptake correlations patterns in the two groups, the present study demonstrated to describe a peculiar metabolic index of behavioral and neurological aspects of MCS complaints. PMID:26438099

  7. [How to localize epigenetics in the landscape of biological research?].

    Science.gov (United States)

    Morange, Michel

    2005-04-01

    Today, epigenetics is a very fashionable field of research. Modification of DNA by methylation, and of chromatin by histone modification or substitution represents a major fraction of the studies; but this special issue shows that epigenetic studies are very diverse, and not limited to the study of chromatin. What is common behind these different uses of the word epigenetics? A brief historical survey shows that epigenetics was invented twice, with different meanings: in the 1940s, by Conrad Waddington, as the study of the relations between the genotype and the phenotype; in the 1960s, as the global mechanisms of gene regulation involved in differentiation and development; what is common is that an approach distinct from genetics was in both cases considered as necessary because genetic models were incapable to address these problems. A good way to appreciate the relations between genetics and epigenetics is to realize that the main aim of organisms is to reproduce, and to consider the way organisms perform this task. Genetics is the precise means organisms have invented to reproduce the structure of their macromolecular components; the genome is also used to control the level and place of this reproduction. All the other means organisms have used to reproduce were more or less the result of tinkering, and constitute the field of epigenetics, with its diversity and richness. PMID:15811300

  8. Epigenetics: new concepts of old phenomena in vascular physiology.

    Science.gov (United States)

    Krause, Bernardo; Sobrevia, Luis; Casanello, Paola

    2009-10-01

    The hypothesis of 'Developmental Origins of Health and Disease' (DOHaD) relies on the presence of mechanisms sensing and signalling a diversity of stimuli during fetal development. The mechanisms that have been broadly suggested to be involved in these processes are the epigenetic modifications that could 'record' perinatal stimuli. Since the definition of epigenetic and the associated mechanisms are conflictive, in this review epigenetic was defined as 'chromosome-based mechanisms that can change the phenotypic plasticity in a cell or organism'. The most understood epigenetic mechanisms (i.e. DNA methylation, histone post-translational modifications (PTM), ATP-dependent chromatin modifications and non-coding RNAs) and reported evidence for their role in fetal programming were briefly reviewed. The development of the vascular system is strongly influenced by epigenetic mechanisms. For that reason vascular cells are good candidates to be explored regarding epigenetic programming since its proved susceptibility to be imprinted. This has been described in pregnancy diseases such as intra-uterine growth restriction, gestational diabetes and pre-eclampsia, where changes in vascular function are preserved in vitro. PMID:19485890

  9. Epigenetic reprogramming of breast cancer cells with oocyte extracts

    Directory of Open Access Journals (Sweden)

    Kumari Rajendra

    2011-01-01

    Full Text Available Abstract Background Breast cancer is a disease characterised by both genetic and epigenetic alterations. Epigenetic silencing of tumour suppressor genes is an early event in breast carcinogenesis and reversion of gene silencing by epigenetic reprogramming can provide clues to the mechanisms responsible for tumour initiation and progression. In this study we apply the reprogramming capacity of oocytes to cancer cells in order to study breast oncogenesis. Results We show that breast cancer cells can be directly reprogrammed by amphibian oocyte extracts. The reprogramming effect, after six hours of treatment, in the absence of DNA replication, includes DNA demethylation and removal of repressive histone marks at the promoters of tumour suppressor genes; also, expression of the silenced genes is re-activated in response to treatment. This activity is specific to oocytes as it is not elicited by extracts from ovulated eggs, and is present at very limited levels in extracts from mouse embryonic stem cells. Epigenetic reprogramming in oocyte extracts results in reduction of cancer cell growth under anchorage independent conditions and a reduction in tumour growth in mouse xenografts. Conclusions This study presents a new method to investigate tumour reversion by epigenetic reprogramming. After testing extracts from different sources, we found that axolotl oocyte extracts possess superior reprogramming ability, which reverses epigenetic silencing of tumour suppressor genes and tumorigenicity of breast cancer cells in a mouse xenograft model. Therefore this system can be extremely valuable for dissecting the mechanisms involved in tumour suppressor gene silencing and identifying molecular activities capable of arresting tumour growth. These applications can ultimately shed light on the contribution of epigenetic alterations in breast cancer and advance the development of epigenetic therapies.

  10. Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction.

    Directory of Open Access Journals (Sweden)

    D Martin Watterson

    Full Text Available Serine-threonine protein kinases are critical to CNS function, yet there is a dearth of highly selective, CNS-active kinase inhibitors for in vivo investigations. Further, prevailing assumptions raise concerns about whether single kinase inhibitors can show in vivo efficacy for CNS pathologies, and debates over viable approaches to the development of safe and efficacious kinase inhibitors are unsettled. It is critical, therefore, that these scientific challenges be addressed in order to test hypotheses about protein kinases in neuropathology progression and the potential for in vivo modulation of their catalytic activity. Identification of molecular targets whose in vivo modulation can attenuate synaptic dysfunction would provide a foundation for future disease-modifying therapeutic development as well as insight into cellular mechanisms. Clinical and preclinical studies suggest a critical link between synaptic dysfunction in neurodegenerative disorders and the activation of p38αMAPK mediated signaling cascades. Activation in both neurons and glia also offers the unusual potential to generate enhanced responses through targeting a single kinase in two distinct cell types involved in pathology progression. However, target validation has been limited by lack of highly selective inhibitors amenable to in vivo use in the CNS. Therefore, we employed high-resolution co-crystallography and pharmacoinformatics to design and develop a novel synthetic, active site targeted, CNS-active, p38αMAPK inhibitor (MW108. Selectivity was demonstrated by large-scale kinome screens, functional GPCR agonist and antagonist analyses of off-target potential, and evaluation of cellular target engagement. In vitro and in vivo assays demonstrated that MW108 ameliorates beta-amyloid induced synaptic and cognitive dysfunction. A serendipitous discovery during co-crystallographic analyses revised prevailing models about active site targeting of inhibitors, providing insights

  11. Epigenetic Control of B Cell Development and B-Cell-Related Immune Disorders.

    Science.gov (United States)

    Bao, Yan; Cao, Xuetao

    2016-06-01

    B lymphocytes are generally recognized as the essential component of humoral immunity and also a regulator of innate immunity. The development of B cells is precisely regulated by a variety of factors via different mechanisms, including cytokine/cytokine receptors, signal transduction molecules, and transcription factors. Recent findings suggest that epigenetic factors, such as DNA methylation, histone modification, and non-coding RNA, play critical roles in establishing B cell lineage-specific gene expression profiles to define and sustain B cell identity and function. Epigenetic modifications are also sensitive to external stimuli and might bridge genetic and environmental factors in the pathogenesis or control of B-cell-related immune disorders, such as autoimmune diseases, lymphoma, and leukemia. Better understanding of the epigenetic mechanisms for regulating B cell development and involving B cell abnormal differentiation and function will shed light on the design of new therapeutic approaches to B-cell-related diseases, and potential candidates of epigenetic modulators may be identified to target epigenetic pathways to prevent or treat B cell disorders. We summarize the relevance of epigenetic marks and landscapes in the stages of B cell development, discuss the interaction of the transcriptional networks and epigenetic changes, and review the involvement of epigenetic risk in the pathogenesis of B-cell-related diseases. Understanding how specific epigenetic alterations contribute to the development of B-cell-related autoimmunity and malignancies is instrumental to control B cell disorders. PMID:26066671

  12. Epigenetics in preimplantation mammalian development.

    Science.gov (United States)

    Canovas, Sebastian; Ross, Pablo Juan

    2016-07-01

    Fertilization is a very dynamic period of comprehensive chromatin remodeling, from which two specialized cells result in a totipotent zygote. The formation of a totipotent cell requires extensive epigenetic remodeling that, although independent of modifications in the DNA sequence, still entails a profound cell-fate change, supported by transcriptional profile modifications. As a result of finely tuned interactions between numerous mechanisms, the goal of fertilization is to form a full healthy new individual. To avoid the persistence of alterations in epigenetic marks, the epigenetic information contained in each gamete is reset during early embryogenesis. Covalent modification of DNA by methylation, as well as posttranslational modifications of histone proteins and noncoding RNAs, appears to be the main epigenetic mechanisms that control gene expression. These allow different cells in an organism to express different transcription profiles, despite each cell containing the same DNA sequence. In the context of replacement of spermatic protamine with histones from the oocyte, active cell division, and specification of different lineages, active and passive mechanisms of epigenetic remodeling have been revealed as critical for editing the epigenetic profile of the early embryo. Importantly, redundant factors and mechanisms are likely in place, and only a few have been reported as critical for fertilization or embryo survival by the use of knockout models. The aim of this review is to highlight the main mechanisms of epigenetic remodeling that ensue after fertilization in mammals. PMID:27165992

  13. Can our understanding of epigenetics assist with primary prevention of congenital defects?

    OpenAIRE

    Martínez-Frías, María-Luisa

    2010-01-01

    Abstract Having identified teratogenic factors, primary prevention of congenital defects is possible by the implementation of specific measures in pregnant women or those planning pregnancy. Our current understanding of the epigenetic processes acting during reproductive events raises new possibilities to prevent both heritable and sporadic congenital anomalies. Cell differentiation during embryonic-foetal development involves different epigenetic processes which, if altered, may a...

  14. Epigenetic methylations and their connections with metabolism.

    Science.gov (United States)

    Chiacchiera, Fulvio; Piunti, Andrea; Pasini, Diego

    2013-05-01

    Metabolic pathways play fundamental roles in several processes that regulate cell physiology and adaptation to environmental changes. Altered metabolic pathways predispose to several different pathologies ranging from diabetes to cancer. Specific transcriptional programs tightly regulate the enzymes involved in cell metabolism and dictate cell fate regulating the differentiation into specialized cell types that contribute to metabolic adaptation in higher organisms. For these reasons, it is of extreme importance to identify signaling pathways and transcription factors that positively and negatively regulate metabolism. Genomic organization allows a plethora of different strategies to regulate transcription. Importantly, large evidence suggests that the quality of diet and the caloric regimen can influence the epigenetic state of our genome and that certain metabolic pathways are also epigenetically controlled reveling a tight crosstalk between metabolism and epigenomes. Here we focus our attention on methylation-based epigenetic reactions, on how different metabolic pathways control these activities, and how these can influence metabolism. Altogether, the recent discoveries linking these apparent distant areas reveal that an exciting field of research is emerging. PMID:23456257

  15. Evolution, epigenetics and cooperation

    Indian Academy of Sciences (India)

    Patrick Bateson

    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.

  16. Chromatin, epigenetics and stem cells.

    Science.gov (United States)

    Roloff, Tim C; Nuber, Ulrike A

    2005-03-01

    Epigenetics is a term that has changed its meaning with the increasing biological knowledge on developmental processes. However, its current application to stem cell biology is often imprecise and is conceptually problematic. This article addresses two different subjects, the definition of epigenetics and chromatin states of stem and differentiated cells. We describe mechanisms that regulate chromatin changes and provide an overview of chromatin states of stem and differentiated cells. Moreover, a modification of the current epigenetics definition is proposed that is not restricted by the heritability of gene expression throughout cell divisions and excludes translational gene expression control. PMID:15819395

  17. Epigenetic modifiers in immunotherapy: a focus on checkpoint inhibitors.

    Science.gov (United States)

    Terranova-Barberio, Manuela; Thomas, Scott; Munster, Pamela N

    2016-06-01

    Immune surveillance should be directed to suppress tumor development and progression, involving a balance of coinhibitory and costimulatory signals that amplify immune response without overwhelming the host. Immunotherapy confers durable clinical benefit in 'immunogenic tumors', whereas in other tumors the responses are modest. Thus, immune checkpoint inhibitors may need to be combined with strategies to boost immune response or increase the tumor immune profile. Epigenetic aberrations contribute significantly to carcinogenesis. Recent findings suggest that epigenetic drugs prime the immune response by increasing expression of tumor-associated antigens and immune-related genes, as well as modulating chemokines and cytokines involved in immune system activation. This review describes our current understanding regarding epigenetic and immunotherapy combination, focusing on immune response priming to checkpoint blockade. PMID:27197539

  18. 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...... with cryopreserved/thawed embryos results in a higher risk of large-for-gestational age babies, which may be due to epigenetic modification. Further animal studies have shown altered gene expression profiles in offspring conceived by ART related to altered glucose metabolism. It is controversial whether human...... adolescents conceived by ART have altered lipid and glucose profiles and thereby a higher long-term risk of cardiovascular disease and diabetes. This commentary describes the basic concepts of epigenetics and gives a short overview of the existing literature on the association between imprinting disorders...

  19. 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...... to molecular phenotypes offers new opportunities to study the genetic (nature) and environmental (nurture) contributions to epigenetic regulation of gene activity during developmental, ageing and disease processes. Besides the classical twin model, the case co-twin design using identical twins discordant...... for a trait or disease is becoming a popular and powerful design for epigenome-wide association study in linking environmental exposure to differential epigenetic regulation and to disease status while controlling for individual genetic make-up. It can be expected that novel uses of twin methods in epigenetic...

  20. 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 * Epigenetics Subject RIV: BO - Biophysics Impact factor: 1.561, year: 2014

  1. 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.

  2. Evaluation of an integrated approach involving chemical and biological processes for the detoxification of gold tailings effluent in Ghana

    International Nuclear Information System (INIS)

    Chemical and bio-remediation measures for the detoxification of pollutants such as cyanide and heavy metals in mine tailings effluent have been developed over the years. The study sought to evaluate the decrease in the concentrations of Cu, Zn, Fe, Cd, As and Pb through the integration of the processes involving photo-oxidation, activated carbon, hydrogen peroxide and bacterial degradation to decontaminate wastewater from the gold ore treatment plant until release into the environment in Ghana. The levels of trace metals Cu (0.345 mg l-1), Zn (0.07 mg l-1) and Fe (0.146 mg l-1 ) in treated effluent released into natural water bodies after bacterial degradation was generally within international and local standards for effluent discharges. Except for As, the levels of Cd and Pb which are hazardous heavy metals that may pose adverse health and environmental effects were within acceptable limits. The toxicity of these metals were in the increasing order Pb < Cd < As. The anthropogenic source of As in the chemically processed arseno-pyritic rock ores of the study area and the marginal 14–49% efficiency of As of the different detoxification processes could have contributed to the high levels of As in the effluent. If optimal conditions are attained for the decontamination processes used, the multi-remediation approach could be an effective solution for the decontamination of mine tailings effluent. (au)

  3. PHYSIC AND CHEMICAL BASIS FOR THE INVOLVEMENT OF D-ELEMENTS OF THE FOURTH GROUP (TITANIUM, ZIRCONIUM, HAFNIUM IN THE SYNTHESIS OF BUILDING AND SILICATE MATERIALS

    Directory of Open Access Journals (Sweden)

    V. I. Bolshakov

    2007-11-01

    Full Text Available In the paper the studies of physico-chemical grounds of involving the fourth group elements (titanium, zirconium, hafnium for syntheses of construction silicate materials are presented. The physico-chemical approach proposed allows involving the great group of technogenic titanium-containing semi-products, concentrates, slags and slimes for production of construction silicate materials and manufacture the products and building structures.

  4. 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. PMID:26822440

  5. The genetics of insomnia--evidence for epigenetic mechanisms?

    Science.gov (United States)

    Palagini, Laura; Biber, Knut; Riemann, Dieter

    2014-06-01

    Sleep is a complex physiological process and still remains one of the great mysteries of science. Over the past 10 y, genetic research has provided a new avenue to address the regulation and function of sleep. Gene loci that contribute quantitatively to sleep characteristics and variability have already been identified. However, up to now, a genetic basis has been established only for a few sleep disorders. Little is yet known about the genetic background of insomnia, one of the most common sleep disorders. According to the conceptualisation of the 3P model of insomnia, predisposing, precipitating and perpetuating factors contribute to the development and maintenance of insomnia. Growing evidence from studies of predisposing factors suggests a certain degree of heritability for insomnia and for a reactivity of sleep patterns to stressful events, explaining the emergence of insomnia in response to stressful life events. While a genetic susceptibility may modulate the impact of stress on the brain, this finding does not provide us with a complete understanding of the capacity of stress to produce long-lasting perturbations of brain and behaviour. Epigenetic gene-environment interactions have been identified just recently and may provide a more complex understanding of the genetic control of sleep and its disorders. It was recently hypothesised that stress-response-related brain plasticity might be epigenetically controlled and, moreover, several epigenetic mechanisms have been assumed to be involved in the regulation of sleep. Hence, it might be postulated that insomnia may be influenced by an epigenetic control process of both sleep mechanisms and stress-response-related gene-environment interactions having an impact on brain plasticity. This paper reviews the evidence for the genetic basis of insomnia and recent theories about epigenetic mechanisms involved in both sleep regulation and brain-stress response, leading to the hypothesis of an involvement of epigenetic

  6. Epigenetic Findings in Autism: New Perspectives for Therapy

    OpenAIRE

    James Jeffrey Bradstreet; Nicola Antonucci; Alessandra Cirillo; Dario Siniscalco

    2013-01-01

    Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, communications, restricted interests, and repetitive stereotypic behaviors. Despite extensive genetic and biological research, significant controversy surrounds our understanding of the specific mechanisms of their pathogenesis. However, accumulating evidence points to the involvement of epigenetic modifications as foundational in creating ASD pathophysiol...

  7. Epigenetic Effects of Cadmium [Abstract and Poster 2014

    Science.gov (United States)

    We have reviewed the literature on in vitro and in vivo experiments as well as human studies on cadmium to understand the epigenetic mechanisms involved in cadmium- induced toxicity and carcinogenicity. This presentation will identify gaps in our current understanding and suggest...

  8. Responses of genes involved in cell cycle control to diverse DNA damaging chemicals in human lung adenocarcinoma A549 cells

    Directory of Open Access Journals (Sweden)

    Gooderham Nigel J

    2005-08-01

    Full Text Available Abstract Background Many anticancer agents and carcinogens are DNA damaging chemicals and exposure to such chemicals results in the deregulation of cell cycle progression. The molecular mechanisms of DNA damage-induced cell cycle alteration are not well understood. We have studied the effects of etoposide (an anticancer agent, cryptolepine (CLP, a cytotoxic alkaloid, benzo [a]pyrene (BaP, a carcinogenic polycyclic aromatic hydrocarbon and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP, a cooked-meat derived carcinogen on the expression of cell cycle regulatory genes to understand the molecular mechanisms of the cell cycle disturbance. Results A549 cells were treated with DMSO or chemicals for up to 72 h and periodically sampled for cell cycle analysis, mRNA and protein expression. DMSO treated cells showed a dominant G1 peak in cell cycle at all times examined. Etoposide and CLP both induced G2/M phase arrest yet the former altered the expression of genes functioning at multiple phases, whilst the latter was more effective in inhibiting the expression of genes in G2-M transition. Both etoposide and CLP induced an accumulation of p53 protein and upregulation of p53 transcriptional target genes. Neither BaP nor PhIP had substantial phase-specific cell cycle effect, however, they induced distinctive changes in gene expression. BaP upregulated the expression of CYP1B1 at 6–24 h and downregulated many cell cycle regulatory genes at 48–72 h. By contrast, PhIP increased the expression of many cell cycle regulatory genes. Changes in the expression of key mRNAs were confirmed at protein level. Conclusion Our experiments show that DNA damaging agents with different mechanisms of action induced distinctive changes in the expression pattern of a panel of cell cycle regulatory genes. We suggest that examining the genomic response to chemical exposure provides an exceptional opportunity to understand the molecular mechanism involved in cellular

  9. Epigenetic processes and cancer risk assessment

    International Nuclear Information System (INIS)

    The U.S. Environmental Protection Agency's Guidelines for Carcinogen Risk Assessment encourages the use of mechanistic data in the assessment of human cancer risk at low (environmental) exposure levels. The key events that define a particular mode of action for tumor formation have been concentrated to date more on mutational responses that are broadly the result of induced DNA damage and enhanced cell proliferation. While it is clear that these processes are important in terms of tumor induction, other modes that fall under the umbrella of epigenetic responses are increasingly being considered to play an important role in susceptibility to tumor induction by environmental chemicals and as significant modifiers of tumor responses. Alterations in gene expression, DNA repair, cell cycle control, genome stability and genome reprogramming could be the result of modification of DNA methylation and chromatin remodeling patterns as a consequence of exposure to environmental chemicals. These concepts are described and discussed

  10. Past, present, and future of epigenetics applied to livestock breeding.

    Science.gov (United States)

    González-Recio, Oscar; Toro, Miguel A; Bach, Alex

    2015-01-01

    This article reviews the concept of Lamarckian inheritance and the use of the term epigenetics in the field of animal genetics. Epigenetics was first coined by Conrad Hal Waddington (1905-1975), who derived the term from the Aristotelian word epigenesis. There exists some controversy around the word epigenetics and its broad definition. It includes any modification of the expression of genes due to factors other than mutation in the DNA sequence. This involves DNA methylation, post-translational modification of histones, but also linked to regulation of gene expression by non-coding RNAs, genome instabilities or any other force that could modify a phenotype. There is little evidence of the existence of transgenerational epigenetic inheritance in mammals, which may commonly be confounded with environmental forces acting simultaneously on an individual, her developing fetus and the germ cell lines of the latter, although it could have an important role in the cellular energetic status of cells. Finally, we review some of the scarce literature on the use of epigenetics in animal breeding programs. PMID:26442117

  11. Carcinogenic effects ofcircadian disruption:an epigenetic viewpoint

    Institute of Scientific and Technical Information of China (English)

    Abbas Salavaty

    2015-01-01

    Circadian rhythms refer to the endogenous rhythms that are generated to synchronize physiology and behavior with 24-h environmental cues. These rhythms are regulated by both external cues and molecular clock mechanisms in almost all cells. Disruption of circadian rhythms, which is called circadian disruption, affects many biological processes within the body and results in different long-term diseases, including cancer. Circadian regulatory pathways result in rhythmic epigenetic modiifcations and the formation of circadian epigenomes. Aberrant epigenetic modiifcations, such as hypermethylation, due to circadian disruption may be involved in the transformation of normal cells into cancer cells. Several studies have indicated an epigenetic basis for the carcinogenic effects of circadian disruption. In this review, I ifrst discuss some of the circadian genes and regulatory proteins. Then, I summarize the current evidence related to the epigenetic modiifcations that result in circadian disruption. In addition, I explain the carcinogenic effects of circadian disruption and highlight its potential role in different human cancers using an epigenetic view-point. Finally, the importance of chronotherapy in cancer treatment is highlighted.

  12. Epigenetic regulation of stemness maintenance in theneurogenic niches

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    In the adult mouse brain, the subventricular zonelining the lateral ventricles and the subgranular zonein the dentate gyrus of the hippocampus are twozones that contain neural stem cells (NSCs) withthe capacity to give rise to neurons and glia duringthe entire life of the animal. Spatial and temporalregulation of gene expression in the NSCs populationis established and maintained by the coordinatedinteraction between transcription factors and epigeneticregulators which control stem cell fate. Epigenetic mechanismsare heritable alterations in genome functionthat do not involve changes in DNA sequence itself butthat modulate gene expression, acting as mediatorsbetween the environment and the genome. At themolecular level, those epigenetic mechanisms comprisechemical modifications of DNA such as methylation,hydroxymethylation and histone modifications neededfor the maintenance of NSC identity. Genomic imprintingis another normal epigenetic process leading to parentalspecificexpression of a gene, known to be implicatedin the control of gene dosage in the neurogenic niches.The generation of induced pluripotent stem cells fromNSCs by expression of defined transcription factors,provide key insights into fundamental principles ofstem cell biology. Epigenetic modifications can alsooccur during reprogramming of NSCs to pluripotencyand a better understanding of this process will helpto elucidate the mechanisms required for stem cellmaintenance. This review takes advantage of recentstudies from the epigenetic field to report knowledgeregarding the mechanisms of stemness maintenance ofneural stem cells in the neurogenic niches.

  13. Potential Epigenetic Mechanism in Non-Alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Chao Sun

    2015-03-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is characterized by excessive fat accumulation in the liver. It ranges from simple steatosis to its more aggressive form, non-alcoholic steatohepatitis (NASH, which may develop into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC if it persists for a long time. However, the exact pathogenesis of NAFLD and the related metabolic disorders remain unclear. Epigenetic changes are stable alterations that take place at the transcriptional level without altering the underlying DNA sequence. DNA methylation, histone modifications and microRNA are among the most common forms of epigenetic modification. Epigenetic alterations are involved in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines, all of which have been implicated in the development and progression of NAFLD. This review summarizes the current advances in the potential epigenetic mechanism of NAFLD. Elucidation of epigenetic factors may facilitate the identification of early diagnositic biomarkers and development of therapeutic strategies for NAFLD.

  14. Epigenetic landscape of amphetamine and methamphetamine addiction in rodents.

    Science.gov (United States)

    Godino, Arthur; Jayanthi, Subramaniam; Cadet, Jean Lud

    2015-01-01

    Amphetamine and methamphetamine addiction is described by specific behavioral alterations, suggesting long-lasting changes in gene and protein expression within specific brain subregions involved in the reward circuitry. Given the persistence of the addiction phenotype at both behavioral and transcriptional levels, several studies have been conducted to elucidate the epigenetic landscape associated with persistent effects of drug use on the mammalian brain. This review discusses recent advances in our comprehension of epigenetic mechanisms underlying amphetamine- or methamphetamine-induced behavioral, transcriptional, and synaptic plasticity. Accumulating evidence demonstrated that drug exposure induces major epigenetic modifications-histone acetylation and methylation, DNA methylation-in a very complex manner. In rare instances, however, the regulation of a specific target gene can be correlated to both epigenetic alterations and behavioral abnormalities. Work is now needed to clarify and validate an epigenetic model of addiction to amphetamines. Investigations that include genome-wide approaches will accelerate the speed of discovery in the field of addiction. PMID:26023847

  15. 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. PMID:27160443

  16. Past, present and future of epigenetics applied to livestock breeding

    Directory of Open Access Journals (Sweden)

    Oscar eGonzalez-Recio

    2015-09-01

    Full Text Available This article reviews the concept of Lamarckian inheritance and the use of the term epigenetics in the field of animal genetics. Epigenetics was first coined by Conrad Hal Waddington (1905-1975, who derived the term from the Aristotelian word epigenesis. There exists some controversy around the word epigenetics and its broad definition. It includes any modification of the expression of genes due to factors other than mutation in the DNA sequence. This involves DNA methylation, post-translational modification of histones, but also linked to regulation of gene expression by non-coding RNAs, genome instabilities or any other force that could modify a phenotype. There is little evidence of the existence of transgenerational epigenetic inheritance in mammals, which may commonly be confounded with environmental forces acting simultaneously on an individual, her developing fetus and the germ cell lines of the latter, although it could have an important role in the cellular energetic status of cells. Finally, we review some of the scarce literature on the use of epigenetics in animal breeding programs.

  17. Low Dose Radiation-Induced Genome and Epigenome Instability Symposium and Epigenetic Mechanisms, DNA Repair, and Chromatin Symposium at the EMS 2008 Annual Meeting - October 2008

    Energy Technology Data Exchange (ETDEWEB)

    Morgan, William F; Kovalchuk, Olga; Dolinoy, Dana C; Dubrova, Yuri E; Coleman, Matthew A; Schär, Primo; Pogribny, Igor; Hendzel, Michael

    2010-02-19

    The Low Dose Radiation Symposium thoughtfully addressed ionizing radiation non-mutational but transmissable alterations in surviving cells. Deregulation of epigenetic processes has been strongly implicated in carcinogenesis, and there is increasing realization that a significant fraction of non-targeted and adaptive mechanisms in response to ionizing radiation are likely to be epigenetic in nature. Much remains to be learned about how chromatin and epigenetic regulators affect responses to low doses of radiation, and how low dose radiation impacts other epigenetic processes. The Epigenetic Mechanisms Symposium focused on on epigenetic mechanisms and their interplay with DNA repair and chromatin changes. Addressing the fact that the most well understood mediators of epigenetic regulation are histone modifications and DNA methylation. Low levels of radiation can lead to changes in the methylation status of certain gene promoters and the expression of DNA methyltransferases, However, epigenetic regulation can also involve changes in higher order chromosome structure.

  18. Shaping the learning curve: epigenetic dynamics in neural plasticity

    Directory of Open Access Journals (Sweden)

    Zohar Ziv Bronfman

    2014-07-01

    Full Text Available A key characteristic of learning and neural plasticity is state-dependent acquisition dynamics reflected by the non-linear learning curve that links increase in learning with practice. Here we propose that the manner by which epigenetic states of individual cells change during learning contributes to the shape of the neural and behavioral learning curve. We base our suggestion on recent studies showing that epigenetic mechanisms such as DNA methylation, histone acetylation and RNA-mediated gene regulation are intimately involved in the establishment and maintenance of long-term neural plasticity, reflecting specific learning-histories and influencing future learning. Our model, which is the first to suggest a dynamic molecular account of the shape of the learning curve, leads to several testable predictions regarding the link between epigenetic dynamics at the promoter, gene-network and neural-network levels. This perspective opens up new avenues for therapeutic interventions in neurological pathologies.

  19. Shaping the learning curve: epigenetic dynamics in neural plasticity

    Science.gov (United States)

    Bronfman, Zohar Z.; Ginsburg, Simona; Jablonka, Eva

    2014-01-01

    A key characteristic of learning and neural plasticity is state-dependent acquisition dynamics reflected by the non-linear learning curve that links increase in learning with practice. Here we propose that the manner by which epigenetic states of individual cells change during learning contributes to the shape of the neural and behavioral learning curve. We base our suggestion on recent studies showing that epigenetic mechanisms such as DNA methylation, histone acetylation, and RNA-mediated gene regulation are intimately involved in the establishment and maintenance of long-term neural plasticity, reflecting specific learning-histories and influencing future learning. Our model, which is the first to suggest a dynamic molecular account of the shape of the learning curve, leads to several testable predictions regarding the link between epigenetic dynamics at the promoter, gene-network, and neural-network levels. This perspective opens up new avenues for therapeutic interventions in neurological pathologies. PMID:25071483

  20. Epigenetic Disregulation in Oral Cancer

    Directory of Open Access Journals (Sweden)

    Stefania Staibano

    2012-02-01

    Full Text Available Squamous cell carcinoma of the oral region (OSCC is one of the most common and highly aggressive malignancies worldwide, despite the fact that significant results have been achieved during the last decades in its detection, prevention and treatment. Although many efforts have been made to define the molecular signatures that identify the clinical outcome of oral cancers, OSCC still lacks reliable prognostic molecular markers. Scientific evidence indicates that transition from normal epithelium to pre-malignancy, and finally to oral carcinoma, depends on the accumulation of genetic and epigenetic alterations in a multistep process. Unlike genetic alterations, epigenetic changes are heritable and potentially reversible. The most common examples of such changes are DNA methylation, histone modification, and small non-coding RNAs. Although several epigenetic changes have been currently linked to OSCC initiation and progression, they have been only partially characterized. Over the last decade, it has been demonstrated that especially aberrant DNA methylation plays a critical role in oral cancer. The major goal of the present paper is to review the recent literature about the epigenetic modifications contribution in early and later phases of OSCC malignant transformation; in particular we point out the current evidence of epigenetic marks as novel markers for early diagnosis and prognosis as well as potential therapeutic targets in oral cancer.

  1. Epigenetics and assisted reproductive technologies.

    Science.gov (United States)

    Pinborg, Anja; Loft, Anne; Romundstad, Liv B; Wennerholm, Ulla-Britt; Söderström-Anttila, Viveca; Bergh, Christina; Aittomäki, Kristiina

    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 associated with ART techniques, but disentangling the influence of the ART procedures per se from the effect of the reproductive disease of the parents is a challenge. Epidemiological human studies have shown altered birthweight profiles in ART compared with spontaneously conceived singletons. Conception with cryopreserved/thawed embryos results in a higher risk of large-for-gestational-age babies, which may be due to epigenetic modification. Further animal studies have shown altered gene expression profiles in offspring conceived by ART related to altered glucose metabolism. It is controversial whether human adolescents conceived by ART have altered lipid and glucose profiles and thereby a higher long-term risk of cardiovascular disease and diabetes. This commentary describes the basic concepts of epigenetics and gives a short overview of the existing literature on the association between imprinting disorders, epigenetic modification and ART. PMID:26458360

  2. The Epigenetic Landscape of Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Emma Conway O’Brien

    2014-01-01

    Full Text Available Acute myeloid leukemia (AML is a genetically heterogeneous disease. Certain cytogenetic and molecular genetic mutations are recognized to have an impact on prognosis, leading to their inclusion in some prognostic stratification systems. Recently, the advent of high-throughput whole genome or exome sequencing has led to the identification of several novel recurrent mutations in AML, a number of which have been found to involve genes concerned with epigenetic regulation. These genes include in particular DNMT3A, TET2, and IDH1/2, involved with regulation of DNA methylation, and EZH2 and ASXL-1, which are implicated in regulation of histones. However, the precise mechanisms linking these genes to AML pathogenesis have yet to be fully elucidated as has their respective prognostic relevance. As massively parallel DNA sequencing becomes increasingly accessible for patients, there is a need for clarification of the clinical implications of these mutations. This review examines the literature surrounding the biology of these epigenetic modifying genes with regard to leukemogenesis and their clinical and prognostic relevance in AML when mutated.

  3. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mann, Monica; Cortez, Valerie [Department of Cellular and Structural Biology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States); Vadlamudi, Ratna K., E-mail: vadlamudi@uthscsa.edu [Department of Obstetrics and Gynecology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States)

    2011-03-29

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications.

  4. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    International Nuclear Information System (INIS)

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications

  5. Epigenetic changes in colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Yan Jia; Mingzhou Guo

    2013-01-01

    Epigenetic changes frequently occur in human colorectal cancer.Genomic global hypomethylation,gene promoter region hypermethylation,histone modifications,and alteration of miRNA patterns are major epigenetic changes in colorectal cancer.Loss of imprinting (LOI) is associated with colorectal neoplasia.Folate deficiency may cause colorectal carcinogenesis by inducing gene-specific hypermethylation and genomic global hypomethylation.HDAC inhibitors and demethylating agents have been approved by the FDA for myelodysplastic syndrome and leukemia treatment.Non-coding RNA is regarded as another kind of epigenetic marker in colorectal cancer.This review is mainly focused on DNA methylation,histone modification,and microRNA changes in colorectal cancer.

  6. Epigenetics in heart failure phenotypes.

    Science.gov (United States)

    Berezin, Alexander

    2016-12-01

    Chronic heart failure (HF) is a leading clinical and public problem posing a higher risk of morbidity and mortality in different populations. HF appears to be in both phenotypic forms: HF with reduced left ventricular ejection fraction (HFrEF) and HF with preserved left ventricular ejection fraction (HFpEF). Although both HF phenotypes can be distinguished through clinical features, co-morbidity status, prediction score, and treatment, the clinical outcomes in patients with HFrEF and HFpEF are similar. In this context, investigation of various molecular and cellular mechanisms leading to the development and progression of both HF phenotypes is very important. There is emerging evidence that epigenetic regulation may have a clue in the pathogenesis of HF. This review represents current available evidence regarding the implication of epigenetic modifications in the development of different HF phenotypes and perspectives of epigenetic-based therapies of HF. PMID:27335803

  7. Epigenetic alterations underlying autoimmune diseases.

    Science.gov (United States)

    Aslani, Saeed; Mahmoudi, Mahdi; Karami, Jafar; Jamshidi, Ahmad Reza; Malekshahi, Zahra; Nicknam, Mohammad Hossein

    2016-03-01

    Recent breakthroughs in genetic explorations have extended our understanding through discovery of genetic patterns subjected to autoimmune diseases (AID). Genetics, on the contrary, has not answered all the conundrums to describe a comprehensive explanation of causal mechanisms of disease etiopathology with regard to the function of environment, sex, or aging. The other side of the coin, epigenetics which is defined by gene manifestation modification without DNA sequence alteration, reportedly has come in to provide new insights towards disease apprehension through bridging the genetics and environmental factors. New investigations in genetic and environmental contributing factors for autoimmunity provide new explanation whereby the interactions between genetic elements and epigenetic modifications signed by environmental agents may be responsible for autoimmune disease initiation and perpetuation. It is aimed through this article to review recent progress attempting to reveal how epigenetics associates with the pathogenesis of autoimmune diseases. PMID:26761426

  8. Epigenetic Epidemiology: Promises for Public Health Research

    OpenAIRE

    Bakulski, Kelly M.; Fallin, M. Daniele

    2014-01-01

    Epigenetic changes underlie developmental and age related biology. Promising epidemiologic research implicates epigenetics in disease risk and progression, and suggests epigenetic status depends on environmental risks as well as genetic predisposition. Epigenetics may represent a mechanistic link between environmental exposures, or genetics, and many common diseases, or may simply provide a quantitative biomarker for exposure or disease for areas of epidemiology currently lacking such measure...

  9. 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....

  10. Restoration of sodic soils involving chemical and biological amendments and phytoremediation by Eucalyptus camaldulensis in a semiarid region.

    Science.gov (United States)

    Seenivasan, R; Prasath, V; Mohanraj, R

    2015-06-01

    Salt-affected soils in semiarid regions impede the agricultural productivity and degrade the ecosystem health. In South India, several hectares of land are salt-affected, where the evapotranspiration exceeds the annual precipitation. This study is an attempt to ameliorate sodic soils, by an experiment involving chemical treatment (addition of gypsum), organic amendments (decomposed bagasse pith and green manuring with Sesbania rostrata) and phytoremediation by plantation of Eucalyptus camaldulensis. The prime focus is to minimize the use of gypsum and improve the soil health in terms of nutrients, microbial population and enzyme activity in addition to sodicity reclamation. At the end of the third year, a reduction of 10 % in soil pH, 33 % in electrical conductivity and 20 % in exchangeable sodium percentage was achieved compared to the initial values. Three- to fourfold increases in organic carbon content were observed. Significant improvement in the available major and micronutrients of soil, microbial growth and enzyme activity was observed, suggesting phytoremediation by E. camaldulensis as a sustainable option for restoration of similar kind of degraded lands. PMID:25547478

  11. Exogenous Nitric Oxide Involved in Subcellular Distribution and Chemical Forms of Cu2+Under Copper Stress in Tomato Seedlings

    Institute of Scientific and Technical Information of China (English)

    DONG Yu-xiu; WANG Xiu-feng; CUI Xiu-min

    2013-01-01

    Nitric oxide (NO), a bioactive signaling molecule, serves as an antioxidant and anti-stress agent under abiotic stress. A hydroponics experiment was conducted to investigate the effects of sodium nitroprusside (SNP), a NO donor, on tomato seedlings exposed to 50 µmol L-1 CuCl2. The results show that copper is primarily stored in the soluble cell sap fraction in the roots, especially after treatment with Cu+SNP treatment, which accounted for 66.2%of the total copper content. The copper concentration gradually decreased from the roots to the leaves. In the leaves, exogenous NO induces the storage of excess copper in the cell walls. Copper stress decreases the proportion of copper integrated with pectates and proteins, but exogenous NO remarkably reverses this trend. The alleviating effect of NO is blocked by hemoglobin. Thus, exogenous NO is likely involved in the regulation of the subcellular copper concentrations and its chemical forms under copper stress. Although exogenous NO inhibited the absorption and transport of excess copper to some extent, the copper accumulation in tomato seedlings signiifcantly increased under copper stress. The use of exogenous NO to enhance copper tolerance in some plants is a promising method for copper remediation.

  12. Epigenetic alterations in gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    In-Seon CHOI; Tsung-Teh WU

    2005-01-01

    Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play important roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpG island methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesis and its relevance of clinical implications.

  13. Epigenetic regulation in cardiac fibrosis

    Institute of Scientific and Technical Information of China (English)

    Li-Ming; Yu; Yong; Xu

    2015-01-01

    Cardiac fibrosis represents an adoptive response in the heart exposed to various stress cues. While resolution of the fibrogenic response heralds normalization of heart function, persistent fibrogenesis is usually associated with progressive loss of heart function and eventually heart failure. Cardiac fibrosis is regulated by a myriad of factors that converge on the transcription of genes encoding extracellular matrix proteins, a process the epigenetic machinery plays a pivotal role. In this minireview, we summarize recent advances regarding the epigenetic regulation of cardiac fibrosis focusing on the role of histone and DNA modifications and non-coding RNAs.

  14. Transgenerational inheritance or resetting of stress-induced epigenetic modifications: two sides of the same coin.

    Directory of Open Access Journals (Sweden)

    Penny J Tricker

    2015-09-01

    Full Text Available The transgenerational inheritance of stress-induced epigenetic modifications is still controversial. Despite several examples of defence ‘priming’ and induced genetic rearrangements, the involvement and persistence of transgenerational epigenetic modifications is not known to be general. Here I argue that non-transmission of epigenetic marks through meiosis may be regarded as an epigenetic modification in itself, and that we should understand the implications for plant evolution in the context of both selection for and selection against transgenerational epigenetic memory. Recent data suggest that both epigenetic inheritance and resetting are mechanistically directed and targeted. Stress-induced epigenetic modifications may buffer against DNA sequence-based evolution to maintain plasticity, or may form part of plasticity’s adaptive potential. To date we have tended to concentrate on the question of whether and for how long epigenetic memory persists. I argue that we should now re-direct our question to investigate the differences between where it persists and where it does not, to understand the higher order evolutionary methods in play and their contribution.

  15. 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....

  16. Review: Epigenetic mechanisms in ocular disease

    OpenAIRE

    He, Shikun; Li, Xiaohua; Chan, Nymph; Hinton, David R.

    2013-01-01

    Epigenetics has become an increasingly important area of biomedical research. Increasing evidence shows that epigenetic alterations influence common pathologic responses including inflammation, ischemia, neoplasia, aging, and neurodegeneration. Importantly, epigenetic mechanisms may have a pathogenic role in many complex eye diseases such as corneal dystrophy, cataract, glaucoma, diabetic retinopathy, ocular neoplasia, uveitis, and age-related macular degeneration. The emerging emphasis on ep...

  17. Epigenetic drift in the aging genome

    DEFF Research Database (Denmark)

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

    2016-01-01

    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 on ...

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

    OpenAIRE

    Groote, De, T.; 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 DNA sequences are uniquely suited to answer such questions and could provide potent (bio)medical tools. Toward the goal of gene-specific GEM by overwriting epigenetic marks (Epigenetic Editing, EGE)...

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

    OpenAIRE

    Groote, de, Robert; 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 DNA sequences are uniquely suited to answer such questions and could provide potent (bio)medical tools. Toward the goal of gene-specific GEM by overwriting epigenetic marks (Epigenetic Editing, EGE)...

  20. Epigenetic modification of OXT and human sociability.

    Science.gov (United States)

    Haas, Brian W; Filkowski, Megan M; Cochran, R Nick; Denison, Lydia; Ishak, Alexandra; Nishitani, Shota; Smith, Alicia K

    2016-07-01

    Across many mammalian species there exist genetic and biological systems that facilitate the tendency to be social. Oxytocin is a neuropeptide involved in social-approach behaviors in humans and others mammals. Although there exists a large, mounting body of evidence showing that oxytocin signaling genes are associated with human sociability, very little is currently known regarding the way the structural gene for oxytocin (OXT) confers individual differences in human sociability. In this study, we undertook a comprehensive approach to investigate the association between epigenetic modification of OXT via DNA methylation, and overt measures of social processing, including self-report, behavior, and brain function and structure. Genetic data were collected via saliva samples and analyzed to target and quantify DNA methylation across the promoter region of OXT We observed a consistent pattern of results across sociability measures. People that exhibit lower OXT DNA methylation (presumably linked to higher OXT expression) display more secure attachment styles, improved ability to recognize emotional facial expressions, greater superior temporal sulcus activity during two social-cognitive functional MRI tasks, and larger fusiform gyrus gray matter volume than people that exhibit higher OXT DNA methylation. These findings provide empirical evidence that epigenetic modification of OXT is linked to several overt measures of sociability in humans and serve to advance progress in translational social neuroscience research toward a better understanding of the evolutionary and genetic basis of normal and abnormal human sociability. PMID:27325757

  1. Mass spectrometry in epigenetic research

    DEFF Research Database (Denmark)

    Beck, Hans Christian

    2010-01-01

    -based proteomics techniques to histone biology has gained new insight into the function of the nucleosome: Novel posttranslational modifications have been discovered at the lateral surface of the nucleosome. These modifications regulate histone-DNA interactions, adding a new dimension to the epigenetic regulation...

  2. 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…

  3. Predicting response to epigenetic therapy

    DEFF Research Database (Denmark)

    Treppendahl, Marianne B; Sommer Kristensen, Lasse; Grønbæk, Kirsten

    2014-01-01

    Drugs targeting the epigenome are new promising cancer treatment modalities; however, not all patients receive the same benefit from these drugs. In contrast to conventional chemotherapy, responses may take several months after the initiation of treatment to occur. Accordingly, identification of ......-approved epigenetic drugs....

  4. 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...

  5. Mitochondrial Epigenetics and Environmental Exposure.

    Science.gov (United States)

    Lambertini, Luca; Byun, Hyang-Min

    2016-09-01

    The rising toll of chronic and debilitating diseases brought about by the exposure to an ever expanding number of environmental pollutants and socio-economic factors is calling for action. The understanding of the molecular mechanisms behind the effects of environmental exposures can lead to the development of biomarkers that can support the public health fields of both early diagnosis and intervention to limit the burden of environmental diseases. The study of mitochondrial epigenetics carries high hopes to provide important biomarkers of exposure and disease. Mitochondria are in fact on the frontline of the cellular response to the environment. Modifications of the epigenetic factors regulating the mitochondrial activity are emerging as informative tools that can effectively report on the effects of the environment on the phenotype. Here, we will discuss the emerging field of mitochondrial epigenetics. This review describes the main epigenetic phenomena that modify the activity of the mitochondrial DNA including DNA methylation, long and short non-coding RNAs. We will discuss the unique pattern of mitochondrial DNA methylation, describe the challenges of correctly measuring it, and report on the existing studies that have analysed the correlation between environmental exposures and mitochondrial DNA methylation. Finally, we provide a brief account of the therapeutic approaches targeting mitochondria currently under consideration. PMID:27344144

  6. Epigenetics of Early Child Development

    Directory of Open Access Journals (Sweden)

    ChrisMurgatroyd

    2011-04-01

    To date, the study of gene-environment interactions in the human population has been dominated by epidemiology. However, recent research in the neuroscience field is now advancing clinical studies by addressing specifically the mechanisms by which gene-environment interactions can predispose individuals towards psychopathology. To this end, appropriate animal models are being developed in which early environmental factors can be manipulated in a controlled manner. Here we will review recent studies performed with the common aim of understanding the effects of the early environment in shaping brain development and discuss the newly developing role of epigenetic mechanisms in translating early life conditions into long-lasting changes in gene expression underpinning brain functions. Particularly, we argue that epigenetic mechanisms can mediate the gene-environment dialogue in early life and give rise to persistent epigenetic programming of adult physiology and dysfunction eventually resulting in disease. Understanding how early life experiences can give raise to lasting epigenetic memories conferring increased risk for mental disorders, how they are maintained and how they could be reversed, is increasingly becoming a focus of modern psychiatry and should pave new guidelines for timely therapeutic interventions.

  7. Epigenetics mechanisms in renal development.

    Science.gov (United States)

    Hilliard, Sylvia A; El-Dahr, Samir S

    2016-07-01

    Appreciation for the role of epigenetic modifications in the diagnosis and treatment of diseases is fast gaining attention. Treatment of chronic kidney disease stemming from diabetes or hypertension as well as Wilms tumor will all profit from knowledge of the changes in the epigenomic landscapes. To do so, it is essential to characterize the epigenomic modifiers and their modifications under normal physiological conditions. The transcription factor Pax2 was identified as a major epigenetic player in the early specification of the kidney. Notably, the progenitors of all nephrons that reside in the cap mesenchyme display a unique bivalent histone signature (expressing repressive epigenetic marks alongside activation marks) on lineage-specific genes. These cells are deemed poised for differentiation and commitment to the nephrogenic lineage. In response to the appropriate inducing signal, these genes lose their repressive histone marks, which allow for their expression in nascent nephron precursors. Such knowledge of the epigenetic landscape and the resultant cell fate or behavior in the developing kidney will greatly improve the overall success in designing regenerative strategies and tissue reprogramming methodologies from pluripotent cells. PMID:26493068

  8. Circadian clocks, epigenetics, and cancer

    KAUST Repository

    Masri, Selma

    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.

  9. Epigenetics of hepatocellular carcinoma: a new horizon

    Institute of Scientific and Technical Information of China (English)

    LIU Wei-ren; SHI Ying-hong; PENG Yuan-fei; FAN Jia

    2012-01-01

    Epigenetic changes refer to stable alterations in gene expression with no underlying modifications in the genetic sequence itself.It has become clear that not only gene variations but also epigenetic modifications may contribute to varied diseases,including cancer.This review will provide an overview of how epigenetic factors,including genomic DNA methylation,histone modifications,and miRNA regulation,contribute to hepatocellular carcinoma (HCC) dissemination,invasion,and metastasis.Additionally,the reversal of dysregulated epigenetic changes has emerged as a potential strategy for the treatment of HCC,and we will summarize the latest epigenetic therapies for HCC.

  10. The ambiguous nature of epigenetic responsibility.

    Science.gov (United States)

    Dupras, Charles; Ravitsky, Vardit

    2016-08-01

    Over the past decade, epigenetic studies have been providing further evidence of the molecular interplay between gene expression and its health outcomes on one hand, and the physical and social environments in which individuals are conceived, born and live on the other. As knowledge of epigenetic programming expands, a growing body of literature in social sciences and humanities is exploring the implications of this new field of study for contemporary societies. Epigenetics has been mobilised to support political claims, for instance, with regard to collective obligations to address socio-environmental determinants of health. The idea of a moral 'epigenetic responsibility' has been proposed, meaning that individuals and/or governments should be accountable for the epigenetic programming of children and/or citizens. However, these discussions have largely overlooked important biological nuances and ambiguities inherent in the field of epigenetics. In this paper, we argue that the identification and assignment of moral epigenetic responsibilities should reflect the rich diversity and complexity of epigenetic mechanisms, and not rely solely on a gross comparison between epigenetics and genetics. More specifically, we explore how further investigation of the ambiguous notions of epigenetic normality and epigenetic plasticity should play a role in shaping this emerging debate. PMID:27015741

  11. 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. PMID:26754591

  12. The Epigenetic Impact of Cruciferous Vegetables on Cancer Prevention

    OpenAIRE

    Royston, Kendra J.; Tollefsbol, Trygve O

    2015-01-01

    The answer to chemoprevention has perhaps been available to the general public since the dawn of time. The epigenetic diet is of extreme interest, for research suggests that cruciferous vegetables are not only an important source of nutrients, but perhaps a key to eliminating cancer as life threatening disease. Cruciferous vegetables such as kale, cabbage, Brussels sprouts, and broccoli sprouts contain chemical components, such as sulforaphane (SFN) and indole-3-carbinol (I3C), which have bee...

  13. 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. PMID:26492160

  14. [Advances in epigenetic researches of Toxoplasma gondii].

    Science.gov (United States)

    Yang, Pei-Liang; Chen, Xiao-Guang

    2012-06-30

    Toxoplasma gondii undergoes a complex life cycle that involves multiple development stages, hosts and environments. The ability to transform from one stage to another and adapt to changing environments demands precise regulation of gene expression. Bioinformatic surveys of the sequenced genomes of T. gondii revealed a peculiar absence of DNA-binding transcription factors that are well-conserved from yeast through humans, but a wealth of epigenetic machinery present in T. gondii. Evidence from reports demonstrates that remodeling of the chromatin structure particularly through post-translational modifications of histones, such as acetylation, methylation, phosphorylation, ubiquitination, and sumoylation, is potentially a major process that coordinates regulation of its gene expression. In addition, no-coding RNAs may play an important role in modulating gene expression of T. gondii. These results provide reliable foundations for prevention of toxoplasmosis by revealing its pathogenic mechanism. PMID:23072142

  15. Benzene exposure is associated with epigenetic changes (Review).

    Science.gov (United States)

    Fenga, Concettina; Gangemi, Silvia; Costa, Chiara

    2016-04-01

    Benzene is a volatile aromatic hydrocarbon solvent and is known as one of the predominant air pollutants in the environment. Chronic exposure to benzene is known to cause aplastic anemia and increased risk of acute myelogenous leukemia in humans. Although the mechanisms by which benzene causes toxicity remain to be fully elucidated, it is widely accepted that its metabolism is crucial to its toxicity, with involvement of one or more reactive metabolites. Novel approaches aimed at evaluating different mechanisms by which benzene can impact on human health by altering gene regulation have been developed. Among these novel approaches, epigenetics appears to be promising. The present review article summarizes the most important findings, reported from the literature, on epigenetic modifications correlated to benzene exposure. A computerized search in PubMed was performed in November 2014, using search terms, including 'benzene', 'epigenetic', 'histone modifications', 'DNA methylation' and 'microRNA'. Epidemiological and experimental studies have demonstrated the potential epigenetic effects of benzene exposure. Several of the epigenomic changes observed in response to environmental exposures may be mechanistically associated with susceptibility to diseases. However, further elucidation of the mechanisms by which benzene alters gene expression may improve prediction of the toxic potential of novel compounds introduced into the environment, and allow for more targeted and appropriate disease prevention strategies. PMID:26936331

  16. The Structural Determinants behind the Epigenetic Role of Histone Variants.

    Science.gov (United States)

    Cheema, Manjinder S; Ausió, Juan

    2015-01-01

    Histone variants are an important part of the histone contribution to chromatin epigenetics. In this review, we describe how the known structural differences of these variants from their canonical histone counterparts impart a chromatin signature ultimately responsible for their epigenetic contribution. In terms of the core histones, H2A histone variants are major players while H3 variant CenH3, with a controversial role in the nucleosome conformation, remains the genuine epigenetic histone variant. Linker histone variants (histone H1 family) haven't often been studied for their role in epigenetics. However, the micro-heterogeneity of the somatic canonical forms of linker histones appears to play an important role in maintaining the cell-differentiated states, while the cell cycle independent linker histone variants are involved in development. A picture starts to emerge in which histone H2A variants, in addition to their individual specific contributions to the nucleosome structure and dynamics, globally impair the accessibility of linker histones to defined chromatin locations and may have important consequences for determining different states of chromatin metabolism. PMID:26213973

  17. The Structural Determinants behind the Epigenetic Role of Histone Variants

    Directory of Open Access Journals (Sweden)

    Manjinder S. Cheema

    2015-07-01

    Full Text Available Histone variants are an important part of the histone contribution to chromatin epigenetics. In this review, we describe how the known structural differences of these variants from their canonical histone counterparts impart a chromatin signature ultimately responsible for their epigenetic contribution. In terms of the core histones, H2A histone variants are major players while H3 variant CenH3, with a controversial role in the nucleosome conformation, remains the genuine epigenetic histone variant. Linker histone variants (histone H1 family haven’t often been studied for their role in epigenetics. However, the micro-heterogeneity of the somatic canonical forms of linker histones appears to play an important role in maintaining the cell-differentiated states, while the cell cycle independent linker histone variants are involved in development. A picture starts to emerge in which histone H2A variants, in addition to their individual specific contributions to the nucleosome structure and dynamics, globally impair the accessibility of linker histones to defined chromatin locations and may have important consequences for determining different states of chromatin metabolism.

  18. Heat-induced release of epigenetic silencing reveals the concealed role of an imprinted plant gene.

    OpenAIRE

    Sanchez, Diego H.; Jerzy Paszkowski

    2014-01-01

    Epigenetic mechanisms suppress the transcription of transposons and DNA repeats; however, this suppression can be transiently released under prolonged heat stress. Here we show that the Arabidopsis thaliana imprinted gene SDC, which is silent during vegetative growth due to DNA methylation, is activated by heat and contributes to recovery from stress. SDC activation seems to involve epigenetic mechanisms but not canonical heat-shock perception and signaling. The heat-mediated transcriptional ...

  19. A tissue biopsy-based epigenetic multiplex PCR assay for prostate cancer detection

    OpenAIRE

    Van Neste Leander; Bigley Joseph; Toll Adam; Otto Gaëtan; Clark James; Delrée Paul; Van Criekinge Wim; Epstein Jonathan I

    2012-01-01

    Abstract Background PSA-directed prostate cancer screening leads to a high rate of false positive identifications and an unnecessary biopsy burden. Epigenetic biomarkers have proven useful, exhibiting frequent and abundant inactivation of tumor suppressor genes through such mechanisms. An epigenetic, multiplex PCR test for prostate cancer diagnosis could provide physicians with better tools to help their patients. Biomarkers like GSTP1, APC and RASSF1 have demonstrated involvement with prosta...

  20. Lung cancer and its association with chronic obstructive pulmonary disease:update on nexus of epigenetics

    OpenAIRE

    Sundar, Isaac K.; Mullapudi, Nandita; Yao, Hongwei; Spivack, Simon D.; Rahman, Irfan

    2011-01-01

    PURPOSE OF REVIEW:Chronic obstructive pulmonary disease (COPD) and lung cancer are the leading causes of morbidity and mortality worldwide. The current research is focused on identifying the common and disparate events involved in epigenetic modifications that concurrently occur during the pathogenesis of COPD and lung cancer. The purpose of this review is to describe the current knowledge and understanding of epigenetic modifications in pathogenesis of COPD and lung cancer.RECENT FINDINGS:Th...

  1. 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.

  2. Diabetes Mellitus and Epigenetic Mechanisms

    Directory of Open Access Journals (Sweden)

    Bekir Engin Eser

    2016-06-01

    Full Text Available Diabetes Mellitus (DM is an important disease caused by insulin deficiency or insulin receptor resistance and characterized by hyperglycemia. The prevalence rate of DM is increasing rapidly worldwide and its associated complications affect the quality of life of patients adverse­ly. In addition, high medical costs for its treatment bring significant economic load on countries. Epigenetics is the reversible modifications on the genome, which lead to changes in gene expression without any alteration in the DNA sequence. Epigenetic modifications can easily be affected by environmental factors and abnormalities in these modifications have been linked to many diseases including cancer and neurodegenerative disorders. In this review, we will summarize the relationship of DM and its complications with DNA and RNA methylation, which are among the most important modifications.

  3. Lifestyle, pregnancy and epigenetic effects.

    Science.gov (United States)

    Barua, Subit; Junaid, Mohammed A

    2015-01-01

    Rapidly growing evidences link maternal lifestyle and prenatal factors with serious health consequences and diseases later in life. Extensive epidemiological studies have identified a number of factors such as diet, stress, gestational diabetes, exposure to tobacco and alcohol during gestation as influencing normal fetal development. In light of recent discoveries, epigenetic mechanisms such as alteration of DNA methylation, chromatin modifications and modulation of gene expression during gestation are believed to possibly account for various types of plasticity such as neural tube defects, autism spectrum disorder, congenital heart defects, oral clefts, allergies and cancer. The purpose of this article is to review a number of published studies to fill the gap in our understanding of how maternal lifestyle and intrauterine environment influence molecular modifications in the offspring, with an emphasis on epigenetic alterations. To support these associations, we highlighted laboratory studies of rodents and epidemiological studies of human based on sampling population cohorts. PMID:25687469

  4. Epigenetic Effects of Cannabis Exposure.

    Science.gov (United States)

    Szutorisz, Henrietta; Hurd, Yasmin L

    2016-04-01

    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 has 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

  5. Crowd behaviour in chemical, biological, radiological and nuclear (CBRN) emergencies: behavioural and psychological responses to incidents involving emergency decontamination

    OpenAIRE

    Carter, Holly Elisabeth

    2014-01-01

    Planning for incidents involving mass decontamination has focused almost exclusively on technical aspects of decontamination, with little attempt to understand public experiences and behaviour. This thesis aimed to examine relevant theory and research, in order to understand public behaviour during incidents involving mass decontamination, and to develop theoretically-derived recommendations for emergency responders. As these incidents involve groups, it was expected that social identity proc...

  6. CHEMICALS

    CERN Multimedia

    Medical Service

    2002-01-01

    It is reminded that all persons who use chemicals must inform CERN's Chemistry Service (TIS-GS-GC) and the CERN Medical Service (TIS-ME). Information concerning their toxicity or other hazards as well as the necessary individual and collective protection measures will be provided by these two services. Users must be in possession of a material safety data sheet (MSDS) for each chemical used. These can be obtained by one of several means : the manufacturer of the chemical (legally obliged to supply an MSDS for each chemical delivered) ; CERN's Chemistry Service of the General Safety Group of TIS ; for chemicals and gases available in the CERN Stores the MSDS has been made available via EDH either in pdf format or else via a link to the supplier's web site. Training courses in chemical safety are available for registration via HR-TD. CERN Medical Service : TIS-ME :73186 or service.medical@cern.ch Chemistry Service : TIS-GS-GC : 78546

  7. Epigenetic changes in tumor microenvironment

    Directory of Open Access Journals (Sweden)

    P Dey

    2011-01-01

    Full Text Available The drama of cancer is not the solo performance of the malignant cells. Microenvironment of the tumor has significant contribution in carcinogenesis. Recent evidences show distinct gene promoter methylation in stromal cells of various malignant and pre-malignant tumors. These changes probably create unique tumor microenvironment, which is responsible for initiation, proliferation, invasion, and metastasis of tumor cells. In this mini review the role of epigenetic changes of tumor microenvironment in carcinogenesis has been discussed.

  8. 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 ostatní: 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

  9. Epigenetic mechanisms in drug addiction

    OpenAIRE

    Renthal, William; Nestler, Eric J.

    2008-01-01

    Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromati...

  10. Epigenetics of the antibody response

    OpenAIRE

    Li, Guideng; Zan, Hong; Xu, Zhenming; Casali, Paolo

    2013-01-01

    Epigenetic marks, such as DNA methylation, histone posttranslational modifications and microRNAs, are induced in B cells by the same stimuli that drive the antibody response. They play major roles in regulating somatic hypermutation (SHM), class switch DNA recombination (CSR) and differentiation to plasma cells or long-lived memory B cells. Histone modifications target the CSR and, possibly, SHM machinery to the immunoglobulin locus; they together with DNA methylation and microRNAs modulate t...

  11. Epigenetic modifications as new targets for liver disease therapies.

    Science.gov (United States)

    Zeybel, Müjdat; Mann, Derek A; Mann, Jelena

    2013-12-01

    An important discovery from the human genome mapping project was that it is comprised of a surprisingly low number of genes,with recent estimates suggesting they are as few as 25,000 [1].This supported an alternative hypothesis that our complexity in comparison with lower order species is likely to be determined by regulatory mechanisms operating at levels above the fundamental DNA sequences of the genome [2]. One set of mechanisms that dictate tissue and cellular complexity can be described by the overarching term "epigenetics". In the 1940s, Conrad Waddington described epigenetics as "the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being". Today we understand epigenetics as a gene regulatory system comprised of 3 major mechanisms including DNA modifications (e.g., methylation), use of histone variants and post-translational modifications of the amino acid tails of histones and non-coding RNAs of which microRNAs are the best characterized [3,4]. Together, these mechanisms orchestrate numerous sets of chemical reactions that switch parts of the genome on and off at specific times and locations.Epigenetic marks, or the epigenome, exhibit a high degree of cellular-specificity and developmental or environmentally driven dynamic plasticity. Due to being at the interface between genome and the environment, the epigenome evolves at a very high rate compared to genetic mutations. Indeed, the differences in the epigenome account for most of the phenotypic uniqueness between closely related species, especially primates. More interestingly,the epigenetic changes, or epimutations, within an individual are not only maintained over cellular generations, but may also be transmitted between generations, such that adaptive epimutations generated in response to a particular environmental cue can influence phenotypes in our children and grandchildren [5]. PMID:23747756

  12. Don't worry; be informed about the epigenetics of anxiety.

    Science.gov (United States)

    Nieto, Steven J; Patriquin, Michelle A; Nielsen, David A; Kosten, Therese A

    2016-01-01

    Epigenetic processes regulate gene expression independent of the DNA sequence and are increasingly being investigated as contributors to the development of behavioral disorders. Environmental insults, such as stress, diet, or toxin exposure, can affect epigenetic mechanisms, including chromatin remodeling, DNA methylation, and non-coding RNAs that, in turn, alter the organism's phenotype. In this review, we examine the literature, derived at both the preclinical (animal) and clinical (human) levels, on epigenetic alterations associated with anxiety disorders. Using animal models of anxiety, researchers have identified epigenetic changes in several limbic and cortical brain regions known to be involved in stress and emotion responses. Environmental manipulations have been imposed prior to conception, during prenatal or early postnatal periods, and at juvenile and adult ages. Time of perturbation differentially affects the epigenome and many changes are brain region-specific. Although some sex-dependent effects are reported in animal studies, more research employing both sexes is needed particularly given that females exhibit a disproportionate number of anxiety disorders. The human literature is in its infancy but does reveal some epigenetic associations with anxiety behaviors and disorders. In particular, effects in monoaminergic systems are seen in line with evidence from etiological and treatment research. Further, there is evidence that epigenetic changes may be inherited to affect subsequent generations. We speculate on how epigenetic processes may interact with genetic contributions to inform prevention and treatment strategies for those who are at risk for or have anxiety disorders. PMID:27189589

  13. Current Advances in Epigenetic Modification and Alteration during Mammalian Ovarian Folliculogenesis

    Institute of Scientific and Technical Information of China (English)

    Zengxiang Pan; Jinbi Zhang; Qifa Li; Yinxia Li; Fangxiong Shi; Zhuang Xie; Honglin Liu

    2012-01-01

    During the growth and development of mammalian ovarian follicles,the activation and deactivation of mass genes are under the synergistic control of diverse modifiers through genetic and epigenetic events.Many factors regulate gene activity and functions through epigenetic modification without altering the DNA sequence,and the common mechanisms may include but arc not limited to: DNA methylation,histone modifications (e.g.,acetylation,deacetylation,phosphorylation,methylation,and ubiquitination),and RNA-associated silencing of gene expression by noncoding RNA.Over the past decade,substantial progress has been achieved in studies involving the epigenetic alterations during mammalian germ cell development.A number of candidate regulatory factors have been identified.This review focuses on the current available information of epigenetic alterations (e.g.,DNA methylation,histone modification,noncoding-RNA-mediated regulation) during mammalian folliculogenesis and recounts when and how epigenetic patterns are differentially established,maintained,or altered in this process.Based on different types of epigenetic regulation,our review follows the temporal progression of events during ovarian folliculogenesis and describes the epigenetic changes and their contributions to germ cell—specific functions at each stage (i.e.,primordial folliculogenesis (follicle formation),follicle maturation,and follicular atresia).

  14. Epigenetic silencing of CYP24 in the tumor microenvironment

    OpenAIRE

    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 fro...

  15. Epigenetic landscape of amphetamine and methamphetamine addiction in rodents

    OpenAIRE

    Godino, Arthur; Jayanthi, Subramaniam; Cadet, Jean Lud

    2015-01-01

    Amphetamine and methamphetamine addiction is described by specific behavioral alterations, suggesting long-lasting changes in gene and protein expression within specific brain subregions involved in the reward circuitry. Given the persistence of the addiction phenotype at both behavioral and transcriptional levels, several studies have been conducted to elucidate the epigenetic landscape associated with persistent effects of drug use on the mammalian brain. This review discusses recent advanc...

  16. Epigenetic Regulation of Autophagy by the Methyltransferase G9a

    OpenAIRE

    Artal-Martinez de Narvajas, Amaia; Gomez, Timothy S.; Zhang, Jin-San; Mann, Alexander O.; Taoda, Yoshiyuki; Gorman, Jacquelyn A.; Herreros-Villanueva, Marta; Gress, Thomas M; Ellenrieder, Volker; Bujanda, Luis; Kim, Do-Hyung; Kozikowski, Alan P.; Koenig, Alexander; Billadeau, Daniel D.

    2013-01-01

    Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the cytoplasmic machinery that orchestrates autophagy induction during starvation, hypoxia, or receptor stimulation has been widely studied, the key epigenetic events that initiate and maintain the autophagy process remain unknown. Here we show that the methyltransferase G9a coordinates the transcriptional activation of key regulators of autophagosome formation by remo...

  17. A Current Genetic and Epigenetic View on Human Aging Mechanisms

    OpenAIRE

    Ostojić, Saša; Pereza, Nina; Kapović, Miljenko

    2009-01-01

    The process of aging is one of the most complex and intruguing biological phenomenons. Aging is a genetically regulated process in which the organism’s maximum lifespan potential is pre-determined, while the rate of aging is influenced by environmental factors and lifestyle. Considering the complexity of mechanisms involved in the regulation of aging process, up to this date there isn’t a major, unifying theory which could explain them. As genetic/epigenetic and environmental factors both ine...

  18. Epigenetic regulation of satellite cell activation during muscle regeneration

    OpenAIRE

    Dilworth, F Jeffrey; Blais, Alexandre

    2011-01-01

    Satellite cells are a population of adult muscle stem cells that play a key role in mediating muscle regeneration. Activation of these quiescent stem cells in response to muscle injury involves modulating expression of multiple developmentally regulated genes, including mediators of the muscle-specific transcription program: Pax7, Myf5, MyoD and myogenin. Here we present evidence suggesting an essential role for the antagonistic Polycomb group and Trithorax group proteins in the epigenetic ma...

  19. Targeting DNA Methylation for Epigenetic Therapy

    Science.gov (United States)

    Yang, Xiaojing; Lay, Fides; Han, Han; Jones, Peter A.

    2010-01-01

    DNA methylation patterns are established during embryonic development and faithfully copied through somatic cell divisions. Based on our understanding of DNA methylation and other interrelated epigenetic modifications, a comprehensive view of the epigenetic landscape and cancer epigenome is evolving. The cancer methylome is highly disrupted, making DNA methylation an excellent target for anti-cancer therapies. During the last few decades, an increasing number of drugs targeting DNA methylation have been developed in an effort to increase efficacy, stability and to decrease toxicity. The earliest and the most successful epigenetic drug to date, 5-Azacytidine, is currently recommended as the first-line treatment for high risk myelodysplastic syndromes (MDS) patients. Encouraging results from clinical trials have prompted further efforts to elucidate epigenetic alterations in cancer and subsequently develop new epigenetic therapies. This review delineates the latest cancer epigenetic models, recent discovery of hypomethylation agents and their application in the clinic. PMID:20846732

  20. Epigenetic alterations of sedimentary rocks at deposits

    International Nuclear Information System (INIS)

    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

  1. 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 ...

  2. Environmental epigenetics and allergic diseases: Recent advances

    OpenAIRE

    Kuriakose, Julie S; Miller, Rachel L.

    2010-01-01

    Significant strides in the understanding of the role of epigenetic regulation in asthma and allergy using both epidemiological approaches as well as experimental ones have been made. This review focuses on new research within the last two years. These include advances in determining how environmental agents implicated in airway disease can induce epigenetic changes, how epigenetic regulation can influence T helper cell (Th) differentiation and T regulatory (Treg) cell production, and new disc...

  3. Epigenetics and the power of art

    OpenAIRE

    Karlic, Heidrun; Baurek, Pia

    2011-01-01

    This review presents an epigenetic view on complex factors leading to development and perception of “genius.” There is increasing evidence which indicates that artistic creativity is influenced by epigenetic processes that act both as targets and mediators of neurotransmitters as well as steroid hormones. Thus, perception and production of art appear to be closely associated with epigenetic contributions to physical and mental health.

  4. Epigenetics modifications and therapeutic prospects in human thyroid cancer

    Directory of Open Access Journals (Sweden)

    Maria Graziella eCatalano

    2012-03-01

    Full Text Available At present no successful treatment is available for advanced thyroid cancer, which comprises poorly differentiated, anaplastic, and metastatic or recurrent differentiated thyroid cancer not responding to radioiodine. In the last few years, biologically targeted therapies for advanced thyroid carcinomas have been proposed on the basis of the recognition of key oncogenic mutations. Although the results of several phase II trials look promising, none of the patients treated had a complete response, and only a minority of them had a partial response, suggesting that the treatment is, at best, effective in stabilizing patients with progressive disease. Epigenetic refers to the study of heritable changes in gene expression that occur without any alteration in the primary DNA sequence. The epigenetic processes establish and maintain the global and local chroma¬tin states that determine gene expression. Epigenetic abnormalities are present in almost all cancers and, together with genetic changes, drive tumour progression. Various genes involved in the control of cell proliferation and invasion (p16INK4A, RASSF1A,PTEN, Rap1GAP, TIMP3, DAPK, RARβ2, E-cadherin, and CITED1 as well as genes specific of thyroid differentiation (Na+/I- symport, TSH receptor, pendrin, SL5A8, and TTF-1 present aberrant methylation in thyroid cancer.This review deals with the most frequent epigenetic alterations in thyroid cancer and focuses on epigenetic therapy, whose goal is to target the chromatin in rapidly dividing tumour cells and potentially restore normal cell functions. Experimental data and clinical trials, especially using deacetylase inhibitors and demethylating agents, are discussed.

  5. Epigenetics and cancer: implications for drug discovery and safety assessment

    International Nuclear Information System (INIS)

    It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Research conducted over the last two decades has led to the paradigm that chemicals can cause cancer either by damaging DNA or by altering cellular growth, probably via receptor-mediated changes in gene expression. However, recent evidence suggests that gene expression can be altered markedly via several diverse epigenetic mechanisms that can lead to permanent or reversible changes in cellular behavior. Key molecular events underlying these mechanisms include the alteration of DNA methylation and chromatin, and changes in the function of cell surface molecules. Thus, for example, DNA methyltransferase enzymes together with chromatin-associated proteins such as histone modifying enzymes and remodelling factors can modify the genetic code and contribute to the establishment and maintenance of altered epigenetic states. This is relevant to many types of toxicity including but not limited to cancer. In this paper, we describe the potential for interplay between genetic alteration and epigenetic changes in cell growth regulation and discuss the implications for drug discovery and safety assessment

  6. Epigenetic changes in cancer as potential targets for prophylaxis and maintenance therapy

    DEFF Research Database (Denmark)

    Grønbæk, Karin Elmegård; Treppendahl, M.; Asmar, F.;

    2008-01-01

    Epigenetic silencing of gene transcription by methylation of DNA or modification of histones is a key event in neoplastic initiation and progression. Alterations of the epigenome have been identified in virtually all types of cancer and involve multiple genes and molecular pathways. Recent studies...... have suggested that epigenetic gene inactivation may represent the first step in tumorigenesis, possibly by affecting the normal differentiation of stem cells and by predisposing these cells to additional oncogenic insults. The mechanisms that drive epigenetic silencing in pre-malignant cells are still...... unknown, but may reflect simple stochastic events that are beneficial to cancer precursor cells. It is now well established that epigenetically silenced genes may be reactivated pharmacologically. Some inhibitors of DNA methyltransferases (5-aza-cytidine and 5-aza-2'-deoxycytidine) or histone deacetylases...

  7. The Evolution of Epigenetics: From Prokaryotes to Humans and Its Biological Consequences

    Science.gov (United States)

    Willbanks, Amber; Leary, Meghan; Greenshields, Molly; Tyminski, Camila; Heerboth, Sarah; Lapinska, Karolina; Haskins, Kathryn; Sarkar, Sibaji

    2016-01-01

    The evolution process includes genetic alterations that started with prokaryotes and now continues in humans. A distinct difference between prokaryotic chromosomes and eukaryotic chromosomes involves histones. As evolution progressed, genetic alterations accumulated and a mechanism for gene selection developed. It was as if nature was experimenting to optimally utilize the gene pool without changing individual gene sequences. This mechanism is called epigenetics, as it is above the genome. Curiously, the mechanism of epigenetic regulation in prokaryotes is strikingly different from that in eukaryotes, mainly higher eukaryotes, like mammals. In fact, epigenetics plays a significant role in the conserved process of embryogenesis and human development. Malfunction of epigenetic regulation results in many types of undesirable effects, including cardiovascular disease, metabolic disorders, autoimmune diseases, and cancer. This review provides a comparative analysis and new insights into these aspects. PMID:27512339

  8. Epigenetic Modulating Agents as a New Therapeutic Approach in Multiple Myeloma

    Energy Technology Data Exchange (ETDEWEB)

    Maes, Ken, E-mail: kemaes@vub.ac.be; Menu, Eline; Van Valckenborgh, Els [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussel (Belgium); Van Riet, Ivan [Stem Cell Laboratory, Department Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussel (Belgium); Vanderkerken, Karin; De Bruyne, Elke, E-mail: kemaes@vub.ac.be [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussel (Belgium)

    2013-04-15

    Multiple myeloma (MM) is an incurable B-cell malignancy. Therefore, new targets and drugs are urgently needed to improve patient outcome. Epigenetic aberrations play a crucial role in development and progression in cancer, including MM. To target these aberrations, epigenetic modulating agents, such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), are under intense investigation in solid and hematological cancers. A clinical benefit of the use of these agents as single agents and in combination regimens has been suggested based on numerous studies in pre-clinical tumor models, including MM models. The mechanisms of action are not yet fully understood but appear to involve a combination of true epigenetic changes and cytotoxic actions. In addition, the interactions with the BM niche are also affected by epigenetic modulating agents that will further determine the in vivo efficacy and thus patient outcome. A better understanding of the molecular events underlying the anti-tumor activity of the epigenetic drugs will lead to more rational drug combinations. This review focuses on the involvement of epigenetic changes in MM pathogenesis and how the use of DNMTi and HDACi affect the myeloma tumor itself and its interactions with the microenvironment.

  9. Epigenetic Modulating Agents as a New Therapeutic Approach in Multiple Myeloma

    International Nuclear Information System (INIS)

    Multiple myeloma (MM) is an incurable B-cell malignancy. Therefore, new targets and drugs are urgently needed to improve patient outcome. Epigenetic aberrations play a crucial role in development and progression in cancer, including MM. To target these aberrations, epigenetic modulating agents, such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), are under intense investigation in solid and hematological cancers. A clinical benefit of the use of these agents as single agents and in combination regimens has been suggested based on numerous studies in pre-clinical tumor models, including MM models. The mechanisms of action are not yet fully understood but appear to involve a combination of true epigenetic changes and cytotoxic actions. In addition, the interactions with the BM niche are also affected by epigenetic modulating agents that will further determine the in vivo efficacy and thus patient outcome. A better understanding of the molecular events underlying the anti-tumor activity of the epigenetic drugs will lead to more rational drug combinations. This review focuses on the involvement of epigenetic changes in MM pathogenesis and how the use of DNMTi and HDACi affect the myeloma tumor itself and its interactions with the microenvironment

  10. Nutrient-gene interactions within one-carbon metabolism and effects on epigenetic regulation through dna methylation in peripheral blood mononuclear cells

    OpenAIRE

    Lotto,

    2010-01-01

    Epigenetics is a field of molecular biology that copes with the study of gene function regulation without variations in DNA structure or nucleotide sequences. Among the main epigenetic phenomema in eukaryotic cells there are DNA methylation and post-traslational mechanisms among which the major are histone methylation and acetylation. Epigenetic changes are potentially reversible phenomena that are controlled also by nutritional factors as the methyl-donors involved in the folate cycle....

  11. Involvement of the ORNL Chemical Technology Division in contaminated air and water handling at the Three Mile Island Nuclear Power Station

    International Nuclear Information System (INIS)

    The President's Commission on the Accident at Three Mile Island requested that Oak Ridge National Laboratory (ORNL) generate documents concerning two areas in which ORNL personnel provided on-site assistance following the accident on March 28, 1979. These are: instrumentation diagnostics, and the treatment of radioactive wastes and liquid effluents stemming from the accident. This report describes the involvement of the ORNL Chemical Technology Division (CTD) in contaminated air and water handling at Three Mile Island

  12. Regulation of the Telomerase Reverse Transcriptase Subunit through Epigenetic Mechanisms

    Science.gov (United States)

    Lewis, Kayla A.; Tollefsbol, Trygve O.

    2016-01-01

    Chromosome-shortening is characteristic of normal cells, and is known as the end replication problem. Telomerase is the enzyme responsible for extending the ends of the chromosomes in de novo synthesis, and occurs in germ cells as well as most malignant cancers. There are three subunits of telomerase: human telomerase RNA (hTERC), human telomerase associated protein (hTEP1), or dyskerin, and human telomerase reverse transcriptase (hTERT). hTERC and hTEP1 are constitutively expressed, so the enzymatic activity of telomerase is dependent on the transcription of hTERT. DNA methylation, histone methylation, and histone acetylation are basic epigenetic regulations involved in the expression of hTERT. Non-coding RNA can also serve as a form of epigenetic control of hTERT. This epigenetic-based regulation of hTERT is important in providing a mechanism for reversibility of hTERT control in various biological states. These include embryonic down-regulation of hTERT contributing to aging and the upregulation of hTERT playing a critical role in over 90% of cancers. Normal human somatic cells have a non-methylated/hypomethylated CpG island within the hTERT promoter region, while telomerase-positive cells paradoxically have at least a partially methylated promoter region that is opposite to the normal roles of DNA methylation. Histone acetylation of H3K9 within the promoter region is associated with an open chromatin state such that transcription machinery has the space to form. Histone methylation of hTERT has varied control of the gene, however. Mono- and dimethylation of H3K9 within the promoter region indicate silent euchromatin, while a trimethylated H3K9 enhances gene transcription. Non-coding RNAs can target epigenetic-modifying enzymes, as well as transcription factors involved in the control of hTERT. An epigenetics diet that can affect the epigenome of cancer cells is a recent fascination that has received much attention. By combining portions of this diet with

  13. A current genetic and epigenetic view on human aging mechanisms.

    Science.gov (United States)

    Ostojić, Sala; Pereza, Nina; Kapović, Miljenko

    2009-06-01

    The process of aging is one of the most complex and intriguing biological phenomenons. Aging is a genetically regulated process in which the organism's maximum lifespan potential is pre-determined, while the rate of aging is influenced by environmental factors and lifestyle. Considering the complexity of mechanisms involved in the regulation of aging process, up to this date there isn't a major, unifying theory which could explain them. As genetic/epigenetic and environmental factors both inevitably influence the aging process, here we present a review on the genetic and epigenetic regulation of the most important molecular and cellular mechanisms involved in the process of aging. Based on the studies on oxidative stress, metabolism, genome stability, epigenetic modifications and cellular senescence in animal models and humans, we give an overview of key genetic and molecular pathways related to aging. As most of genetic manipulations which influence the aging process also affect reproduction, we discuss aging in humans as a post-reproductive genetically determined process. After the age of reproductive success, aging continously progresses which clinically coincides with the onset of most chronic diseases, cancers and dementions. As evolution shapes the genomes for reproductive success and not for post-reproductive survival, aging could be defined as a protective mechanism which ensures the preservation and progress of species through the modification, trasmission and improvement of genetic material. PMID:19662799

  14. Epigenetics of Stress, Addiction, and Resilience: Therapeutic Implications.

    Science.gov (United States)

    Cadet, Jean Lud

    2016-01-01

    Substance use disorders (SUDs) are highly prevalent. SUDs involve vicious cycles of binges followed by occasional periods of abstinence with recurrent relapses despite treatment and adverse medical and psychosocial consequences. There is convincing evidence that early and adult stressful life events are risks factors for the development of addiction and serve as cues that trigger relapses. Nevertheless, the fact that not all individuals who face traumatic events develop addiction to licit or illicit drugs suggests the existence of individual and/or familial resilient factors that protect these mentally healthy individuals. Here, I give a brief overview of the epigenetic bases of responses to stressful events and of epigenetic changes associated with the administration of drugs of abuse. I also discuss the psychobiology of resilience and alterations in epigenetic markers that have been observed in models of resilience. Finally, I suggest the possibility that treatment of addiction should involve cognitive and pharmacological approaches that enhance resilience in at risk individuals. Similar approaches should also be used with patients who have already succumbed to the nefarious effects of addictive substances. PMID:25502297

  15. An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis

    Science.gov (United States)

    Matkar, Smita; Sharma, Paras; Gao, Shubin; Gurung, Buddha; Katona, Bryson W; Liao, Jennifer; Muhammad, Abdul Bari; Kong, Xiang-Cheng; Wang, Lei; Jin, Guanghui; Dang, Chi; Hua, Xianxin

    2016-01-01

    SUMMARY Human epidermal growth factor receptor 2 (HER2) is upregulated in a subset of human breast cancers. However, the cancer cells often quickly develop an adaptive response to HER2 kinase inhibitors. We found that an epigenetic pathway involving MLL2 is crucial for growth of HER2+ cells and MLL2 reduces sensitivity of the cancer cells to a HER2 inhibitor, Lapatinib. Lapatinib-induced FOXO transcription factors, normally tumor-suppressing, paradoxically upregulate c-Myc epigenetically, in concert with a cascade of MLL2-associating epigenetic regulators, to dampen sensitivity of the cancer cells to Lapatinib. An epigenetic inhibitor suppressing c-Myc synergizes with Lapatinib to suppress cancer growth in vivo, partly by repressing the FOXO/c-Myc axis, unraveling an epigenetically regulated FOXO/c-Myc axis as a potential target to improve therapy. PMID:26461093

  16. The epigenetic role of vitamin C in health and disease.

    Science.gov (United States)

    Camarena, Vladimir; Wang, Gaofeng

    2016-04-01

    Recent advances have uncovered a previously unknown function of vitamin C in epigenetic regulation. Vitamin C exists predominantly as an ascorbate anion under physiological pH conditions. Ascorbate was discovered as a cofactor for methylcytosine dioxygenases that are responsible for DNA demethylation, and also as a likely cofactor for some JmjC domain-containing histone demethylases that catalyze histone demethylation. Variation in ascorbate bioavailability thus can influence the demethylation of both DNA and histone, further leading to different phenotypic presentations. Ascorbate deficiency can be presented systematically, spatially and temporally in different tissues at the different stages of development and aging. Here, we review how ascorbate deficiency could potentially be involved in embryonic and postnatal development, and plays a role in various diseases such as neurodegeneration and cancer through epigenetic dysregulation. PMID:26846695

  17. Linking DNA replication to heterochromatin silencing and epigenetic inheritance

    Institute of Scientific and Technical Information of China (English)

    Qing Li; Zhiguo Zhang

    2012-01-01

    Chromatin is organized into distinct functional domains.During mitotic cell division,both genetic information encoded in DNA sequence and epigenetic information embedded in chromatin structure must be faithfully duplicated.The inheritance of epigenetic states is critical in maintaining the genome integrity and gene expression state.In this review,we will discuss recent progress on how proteins known to be involved in DNA replication and DNA replication-coupled nucleosome assembly impact on the inheritance and maintenance of heterochromatin,a tightly compact chromatin structure that silences gene transcription.As heterochromatin is important in regulating gene expression and maintaining genome stability,understanding how heterochromatin states are inherited during S phase of the cell cycle is of fundamental importance.

  18. Textbook Forum: Equilibrium Constants of Chemical Reactions Involving Condensed Phases: Pressure Dependence and Choice of Standard State.

    Science.gov (United States)

    Perlmutter-Hayman, Berta

    1984-01-01

    Problems of equilibria in condensed phases (particularly those involving solutes in dilute solutions) are encountered by students in their laboratory work; the thermodynamics of these equilibria is neglected in many textbooks. Therefore, several aspects of this topic are explored, focusing on pressure dependence and choice of standard state. (JN)

  19. On the origin of sperm epigenetic heterogeneity.

    Science.gov (United States)

    Laurentino, Sandra; Borgmann, Jennifer; Gromoll, Jörg

    2016-05-01

    The influence of epigenetic modifications on reproduction and on the function of male germ cells has been thoroughly demonstrated. In particular, aberrant DNA methylation levels in sperm have been associated with abnormal sperm parameters, lower fertilization rates and impaired embryo development. Recent reports have indicated that human sperm might be epigenetically heterogeneous and that abnormal DNA methylation levels found in the sperm of infertile men could be due to the presence of sperm populations with different epigenetic quality. However, the origin and the contribution of different germ cell types to this suspected heterogeneity remain unclear. In this review, we focus on sperm epigenetics at the DNA methylation level and its importance in reproduction. We take into account the latest developments and hypotheses concerning the functional significance of epigenetic heterogeneity coming from the field of stem cell and cancer biology and discuss the potential importance and consequences of sperm epigenetic heterogeneity for reproduction, male (in)fertility and assisted reproductive technologies (ART). Based on the current information, we propose a model in which spermatogonial stem cell variability, either intrinsic or due to external factors (such as endocrine action and environmental stimuli), can lead to epigenetic sperm heterogeneity, sperm epimutations and male infertility. The elucidation of the precise causes for epimutations, the conception of adequate therapeutic options and the development of sperm selection technologies based on epigenetic quality should be regarded as crucial to the improvement of ART outcome in the near future. PMID:26884419

  20. 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...

  1. 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 ...

  2. Orchestrating epigenetic roles targeting ocular tumors

    Directory of Open Access Journals (Sweden)

    Wen X

    2016-02-01

    Full Text Available Xuyang Wen*, Linna Lu*, He Zhang, Xianqun Fan Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Epigenetics is currently one of the most promising areas of study in the field of biomedical research. Scientists have dedicated their efforts to studying epigenetic mechanisms in cancer for centuries. Additionally, the field has expanded from simply studying DNA methylation to other areas, such as histone modification, non-coding RNA, histone variation, nucleosome location, and chromosome remodeling. In ocular tumors, a large amount of epigenetic exploration has expanded from single genes to the genome-wide level. Most importantly, because epigenetic changes are reversible, several epigenetic drugs have been developed for the treatment of cancer. Herein, we review the current understanding of epigenetic mechanisms in ocular tumors, including but not limited to retinoblastoma and uveal melanoma. Furthermore, the development of new pharmacological strategies is summarized. Keywords: ocular tumors, epigenetics, retinoblastoma, uveal melanoma, epigenetic drugs

  3. Epigenetics, estradiol, and hippocampal memory consolidation

    OpenAIRE

    Frick, Karyn M.

    2013-01-01

    Epigenetic alterations of histone proteins and DNA are essential for hippocampal synaptic plasticity and cognitive function, and contribute to the etiology of psychiatric disorders and neurodegenerative diseases. Hippocampal memory formation depends on histone alterations and DNA methylation, and increasing evidence suggests that regulation of these epigenetic processes by modulatory factors such as environmental enrichment, stress, and hormones substantially influences memory function. Recen...

  4. Epigenetic associations in relation to cardiovascular prevention and therapeutics.

    Science.gov (United States)

    Voelter-Mahlknecht, Susanne

    2016-01-01

    Cardiovascular diseases (CVD) increasingly burden societies with vast financial and health care problems. Therefore, the importance of improving preventive and therapeutic measures against cardiovascular diseases is continually growing. To accomplish such improvements, research must focus particularly on understanding the underlying mechanisms of such diseases, as in the field of epigenetics, and pay more attention to strengthening primary prevention. To date, preliminary research has found a connection between DNA methylation, histone modifications, RNA-based mechanisms and the development of CVD like atherosclerosis, cardiac hypertrophy, myocardial infarction, and heart failure. Several therapeutic agents based on the findings of such research projects are currently being tested for use in clinical practice. Although these tests have produced promising data so far, no epigenetically active agents or drugs targeting histone acetylation and/or methylation have actually entered clinical trials for CVDs, nor have they been approved by the FDA. To ensure the most effective prevention and treatment possible, further studies are required to understand the complex relationship between epigenetic regulation and the development of CVD. Similarly, several classes of RNA therapeutics are currently under development. The use of miRNAs and their targets as diagnostic or prognostic markers for CVDs is promising, but has not yet been realized. Further studies are necessary to improve our understanding of the involvement of lncRNA in regulating gene expression changes underlying heart failure. Through the data obtained from such studies, specific therapeutic strategies to avoid heart failure based on interference with incRNA pathways could be developed. Together, research and testing findings raise hope for enhancing the therapeutic armamentarium. This review presents the currently available data concerning epigenetic mechanisms and compounds involved in cardiovascular diseases

  5. Epigenetic field cancerization in gastrointestinal cancers.

    Science.gov (United States)

    Baba, Yoshifumi; Ishimoto, Takatsugu; Kurashige, Junji; Iwatsuki, Masaaki; Sakamoto, Yasuo; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo

    2016-06-01

    Epigenetic alterations, including aberrant DNA methylation, play an important role in human cancer development. Importantly, epigenetic alterations are reversible and can be targets for therapy or chemoprevention for various types of human cancers. A field for cancerization, or a field defect, is formed by the accumulation of genetic and/or epigenetic alterations in normal-appearing tissues and can correlate with risk of cancer development. Thus, a better understanding of epigenetic field cancerization may represent a useful translational opportunity for cancer risk assessment, including previous history and exposure to carcinogenic factors, and for cancer prevention. In this article, we summarize current knowledge regarding epigenetic field cancerization and its clinical implications in gastrointestinal cancers, including colorectal cancer, gastric cancer and esophageal cancer. PMID:26971491

  6. 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.

  7. 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...

  8. Epigenetic regulation of skeletal muscle metabolism.

    Science.gov (United States)

    Howlett, Kirsten F; McGee, Sean L

    2016-07-01

    Normal skeletal muscle metabolism is essential for whole body metabolic homoeostasis and disruptions in muscle metabolism are associated with a number of chronic diseases. Transcriptional control of metabolic enzyme expression is a major regulatory mechanism for muscle metabolic processes. Substantial evidence is emerging that highlights the importance of epigenetic mechanisms in this process. This review will examine the importance of epigenetics in the regulation of muscle metabolism, with a particular emphasis on DNA methylation and histone acetylation as epigenetic control points. The emerging cross-talk between metabolism and epigenetics in the context of health and disease will also be examined. The concept of inheritance of skeletal muscle metabolic phenotypes will be discussed, in addition to emerging epigenetic therapies that could be used to alter muscle metabolism in chronic disease states. PMID:27215678

  9. Implications of epigenetic mechanisms in the development and treatment of personality disorders.

    Science.gov (United States)

    Lorea-Conde, Iñaki; Molero, Patricio

    2015-01-01

    Epigenetics deals with the genic expression processes that do not involve modifications of the DNA sequence, that is, focuses on the different trajectories of a given genotype throughout the organism’s lifespan. These processes are involved in basic biological functions such as the cellular differentiation or sexual selection, in the development of complex diseases such as Rett’s syndrome and in psychiatric disorders such as schizophrenia and depression among others. Epigenetic studies are yielding evidence that environmental events and psychosocial factors can modify the epigenome. This work reviews studies analyzing the influence of environmental factors involved in the pathogenesis of behavioral features and phenotypic expression of personality disorder’s symptomatic domains, such as late onset affective symptoms related with early adverse events in childhood and dysfunction of stress modulation mechanisms. In addition, the knowledge of these epigenetic mechanisms may contribute to the identification of novel both psychotherapeutic and pharmacological therapeutic targets for the treatment of personality disorders. PMID:25812541

  10. Epigenetic regulation of iron homeostasis in Arabidopsis.

    Science.gov (United States)

    Xing, Jiewen; Wang, Tianya; Ni, Zhongfu

    2015-01-01

    Iron (Fe) is one of the most important microelement required for plant growth and development because of its unique property of catalyzing oxidation/reduction reactions. Iron deficiency impairs fundamental processes which could lead to a decrease in chlorophyll production and pollen fertility, thus influencing crop productivity and quality. However, iron in excess is toxic to the cell and is harmful to the plant. To exactly control the iron content in all tissues, plants have evolved many strategies to regulate iron homeostasis, which refers to 2 successive steps: iron uptake at the root surface, and iron distribution in vivo. In the last decades, a number of transporters and regulatory factors involved in this process have been isolated and identified. To cope with the complicated flexible environmental conditions, plants apply diverse mechanisms to regulate the expression and activity of these components. One of the most important mechanisms is epigenetic regulation of iron homeostasis. This review has been presented to provide an update on the information supporting the involvement of histone modifications in iron homeostasis and possible future course of the field. PMID:26313698

  11. Epigenetic regulation of iron homeostasis in Arabidopsis

    Science.gov (United States)

    Xing, Jiewen; Wang, Tianya; Ni, Zhongfu

    2015-01-01

    Iron (Fe) is one of the most important microelement required for plant growth and development because of its unique property of catalyzing oxidation/reduction reactions. Iron deficiency impairs fundamental processes which could lead to a decrease in chlorophyll production and pollen fertility, thus influencing crop productivity and quality. However, iron in excess is toxic to the cell and is harmful to the plant. To exactly control the iron content in all tissues, plants have evolved many strategies to regulate iron homeostasis, which refers to 2 successive steps: iron uptake at the root surface, and iron distribution in vivo. In the last decades, a number of transporters and regulatory factors involved in this process have been isolated and identified. To cope with the complicated flexible environmental conditions, plants apply diverse mechanisms to regulate the expression and activity of these components. One of the most important mechanisms is epigenetic regulation of iron homeostasis. This review has been presented to provide an update on the information supporting the involvement of histone modifications in iron homeostasis and possible future course of the field. PMID:26313698

  12. Interaction of 2-aminopyrimidine with σ- and π-acceptors involving chemical reactions via initial charge transfer complexation

    Science.gov (United States)

    Rabie, U. M.; Abou-El-Wafa, M. H.; Mohamed, R. A.

    2007-12-01

    Interaction of 2-aminopyrimidine (AP) with iodine as a typical σ-type acceptor and with a typical π-type acceptor, 2,3,5,6-tetrachloro-1,4-benzoquinone, p-chloranil (CHL) have been studied spectrophotometrically. Electronic absorption spectra of the system AP-I 2 in several organic solvents of different polarities have performed clear charge transfer (CT) band(s). Formation constants ( KCT) and molar absorption coefficients ( ɛCT) and thermodynamic properties, Δ H, Δ S, and Δ G, of this system in various organic solvents were determined and discussed. Interaction of AP with the π-acceptor has shown unique behaviors. Chemical reaction has occurred via prior or initial formation of the outer-sphere CT complex followed by formation of the corresponding anion radicals, CHL rad - , as intermediates. UV-vis, 1H NMR, Mass, and FT-IR spectra in addition to the elemental analysis were used to confirm the proposed occurrence of the chemical reaction and to investigate the synthesized solid products.

  13. MicroRNAs as new Characters in the Plot between Epigenetics and Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Alessio ePaone

    2011-09-01

    Full Text Available Prostate cancer (PCA still represents a leading cause of death. An increasing number of studies have documented that microRNAs (miRNAs, a subgroup of non-coding RNAs with gene regulatory functions, are differentially expressed in PCA respect to the normal tissue counterpart, suggesting their involvement in prostate carcinogenesis and dissemination. Interestingly, it has been shown that miRNAs undergo the same regulatory mechanisms than any other protein coding gene, including epigenetic regulation. In turn, miRNAs can also affect the expression of oncogenes and tumor suppressor genes by targeting effectors of the epigenetic machinery, therefore indirectly affecting the epigenetic controls on these genes. Among the genes that undergo this complex regulation, there is the androgen receptor (AR, a key therapeutic target for PCA. This review will focus on the role of epigenetically regulated and epigenetically regulating miRNAs in prostate cancer and on the fine regulation of AR expression, as mediated by this miRNA-epigenetics interaction.

  14. Combinatorial epigenetic deregulation by Helicobacter pylori and Epstein-Barr virus infections in gastric tumourigenesis.

    Science.gov (United States)

    Wu, William Kk; Yu, Jun; Chan, Matthew Tv; To, Ka F; Cheng, Alfred Sl

    2016-07-01

    Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodelling and microRNAs, convert environmental signals to transcriptional outputs but are commonly hijacked by pathogenic microorganisms. Recent advances in cancer epigenomics have shed new light on the importance of epigenetic deregulation in Helicobacter pylori- and Epstein-Barr virus (EBV)-driven gastric tumourigenesis. Moreover, it is becoming apparent that epigenetic mechanisms interact through crosstalk and feedback loops, which modify global gene expression patterns. The SWI/SNF remodelling complexes are commonly involved in gastric cancers associated with H. pylori or EBV through different mechanisms, including microRNA-mediated deregulation and genetic mutations. While H. pylori causes epigenetic silencing of tumour-suppressor genes to deregulate cellular pathways, EBV-positive tumours exhibit a widespread and distinctive DNA hypermethylation profile. Given the early successes of epigenetic drugs in haematological malignancies, further studies are mandated to enrich and translate our understanding of combinatorial epigenetic deregulation in gastric cancers into interventional strategies in the clinic. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27102722

  15. Heterogeneity of epigenetic changes at ischemia/reperfusion- and endotoxin-induced acute kidney injury genes.

    Science.gov (United States)

    Mar, Daniel; Gharib, Sina A; Zager, Richard A; Johnson, Ali; Denisenko, Oleg; Bomsztyk, Karol

    2015-10-01

    Aberrant gene expression is a molecular hallmark of acute kidney injury (AKI). As epigenetic processes control gene expression in a cell- and environment-defined manner, understanding the epigenetic pathways that regulate genes altered by AKI may open vital new insights into the complexities of disease pathogenesis and identify possible therapeutic targets. Here we used matrix chromatin immunoprecipitation and integrative analysis to study 20 key permissive and repressive epigenetic histone marks at transcriptionally induced Tnf, Ngal, Kim-1, and Icam-1 genes in mouse models of AKI; unilateral renal ischemia/reperfusion, lipopolysaccharide (LPS), and their synergistically injurious combination. Results revealed unexpected heterogeneity of transcriptional and epigenetic responses. Tnf and Ngal were transcriptionally upregulated in response to both treatments individually, and to combination treatment. Kim-1 was induced by ischemia/reperfusion and Icam-1 by LPS only. Epigenetic alterations at these genes exhibited distinct time-dependent changes that shared some similarities, such as reduction in repressive histone modifications, and also had major ischemia/reperfusion versus endotoxin differences. Thus, diversity of changes at AKI genes in response to different insults indicates involvement of several epigenetic pathways. This could be exploited pharmacologically through rational-drug design to alter the course and improve clinical outcomes of this syndrome. PMID:26061546

  16. Trichinella spiralis, potential model nematode for epigenetics and its implication in metazoan parasitism

    Directory of Open Access Journals (Sweden)

    Fei eGAO

    2014-01-01

    Full Text Available The recent discovery of DNA methylation in the nematode T. spiralis may raise the possibility of using it as a potential model organism for epigenetic studies instead of C. elegans, which is deficient in this important epigenetic modification. In contrast to the free-living nematode C. elegans, T. spiralis is a parasitic worm that possesses a complicated life cycle and undergoes a complex developmental regulation of genes. We emphasise that the differential methylomes in the different life-history stages of T. spiralis can provide insight on how DNA methylation is triggered and regulated. In particular, we have demonstrated that DNA methylation is involved in the regulation of its parasitism-related genes. Further computational analyses indicated that the regulatory machinery for DNA methylation can also be found in the T. spiralis genome. By a logical extension of this point, we speculate that comprehensively addressing the epigenetic machinery of T. spiralis may help to understand epigenetics in invertebrates. Furthermore, considering the implication of epigenetics in metazoan parasitism, using T. spiralis as an epigenetic model organism may further contribute to drug development against metazoan parasites.

  17. Interindividual variability in stress susceptibility: A role for epigenetic mechanisms in PTSD

    Directory of Open Access Journals (Sweden)

    J.DavidSweatt

    2013-06-01

    Full Text Available Post-traumatic stress disorder (PTSD is a psychiatric condition characterized by intrusive and persistent memories of a psychologically traumatic event that leads to significant functional and social impairment in affected individuals. The molecular bases underlying persistent outcomes of a transient traumatic event have remained elusive for many years, but recent studies in rodents have implicated epigenetic modifications of chromatin structure and DNA methylation as fundamental mechanisms for the induction and stabilization of fear memory. In addition to mediating adaptations to traumatic events that ultimately cause PTSD, epigenetic mechanisms are also involved in establishing individual differences in PTSD risk and resilience by mediating long-lasting effects of genes and early environment on adult function and behavior. In this review, we discuss the current evidence for epigenetic regulation of PTSD in human studies and in animal models and comment on ways in which these models can be expanded. In addition, we identify key outstanding questions in the study of epigenetic mechanisms of PTSD in the context of rapidly evolving technologies that are constantly updating and adjusting our understanding of epigenetic modifications and their functional roles. Finally, we discuss the potential application of epigenetic approaches in identifying markers of risk and resilience that can be utilized to promote early intervention and develop therapeutic strategies to combat PTSD after symptom onset.

  18. 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.

  19. Epigenetic Findings in Autism: New Perspectives for Therapy

    Directory of Open Access Journals (Sweden)

    James Jeffrey Bradstreet

    2013-09-01

    Full Text Available Autism and autism spectrum disorders (ASDs are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, communications, restricted interests, and repetitive stereotypic behaviors. Despite extensive genetic and biological research, significant controversy surrounds our understanding of the specific mechanisms of their pathogenesis. However, accumulating evidence points to the involvement of epigenetic modifications as foundational in creating ASD pathophysiology. Epigenetic modifications or the alteration of DNA transcription via variations in DNA methylation and histone modifications but without alterations in the DNA sequence, affect gene regulation. These alterations in gene expression, obtained through DNA methylation and/or histone modifications, result from transcriptional regulatory influences of environmental factors, such as nutritional deficiencies, various toxicants, immunological effects, and pharmaceuticals. As such these effects are epigenetic regulators which determine the final biochemistry and physiology of the individual. In contrast to psychopharmacological interventions, bettering our understanding of how these gene-environmental interactions create autistic symptoms should facilitate the development of therapeutic targeting of gene expression for ASD biomedical care.

  20. Epigenetic mechanisms mediating vulnerability and resilience to psychiatric disorders.

    Science.gov (United States)

    Dudley, Kevin J; Li, Xiang; Kobor, Michael S; Kippin, Tod E; Bredy, Timothy W

    2011-06-01

    The impact that stressful encounters have upon long-lasting behavioural phenotypes is varied. Whereas a significant proportion of the population will develop "stress-related" conditions such as post-traumatic stress disorder or depression in later life, the majority are considered "resilient" and are able to cope with stress and avoid such psychopathologies. The reason for this heterogeneity is undoubtedly multi-factorial, involving a complex interplay between genetic and environmental factors. Both genes and environment are of critical importance when it comes to developmental processes, and it appears that subtle differences in either of these may be responsible for altering developmental trajectories that confer vulnerability or resilience. At the molecular level, developmental processes are regulated by epigenetic mechanisms, with recent clinical and pre-clinical data obtained by ourselves and others suggesting that epigenetic differences in various regions of the brain are associated with a range of psychiatric disorders, including many that are stress-related. Here we provide an overview of how these epigenetic differences, and hence susceptibility to psychiatric disorders, might arise through exposure to stress-related factors during critical periods of development. PMID:21251925

  1. Nutrition in emergencies: Issues involved in ensuring proper nutrition in post-chemical, biological, radiological, and nuclear disaster

    Directory of Open Access Journals (Sweden)

    Som Nath Singh

    2010-01-01

    Full Text Available Accidental or deliberate exposure to chemical, biological, radiological, and nuclear (CBRN agents poses considerable threat throughout the world. Under such conditions, ensuring proper nutrition is a difficult task due to contamination of food available in the affected area. Generally, food is not prepared or served in an environment contaminated by CBRN agents. Foods that are properly packed need to be decontaminated from outside before use. These agents get incorporated in to food chain. Therefore, especially the foliage vegetables, milk and meat products from affected area are not fit for consumption. Potassium iodide has protective role, as radioiodine uptake into the thyroid can be blocked by its pharmacological doses. This is most effective when taken before exposure, but still has significant effects up to five to six hours postexposure. The antioxidant vitamins and minerals may be included in therapeutic feeding programs, as they are known to protect against oxidative stress. Minimum requirement of calories and nutrients are similar to other disasters and are discussed in the present review.

  2. Epigenetic Regulation of Cholesterol Homeostasis

    Directory of Open Access Journals (Sweden)

    Steve eMeaney

    2014-09-01

    Full Text Available Although best known as a risk factor for cardiovascular disease, cholesterol is a vital component of all mammalian cells. In addition to key structural roles, cholesterol is a vital biochemical precursor for numerous biologically important compounds including oxysterols and bile acids, as well as acting as an activator of critical morphogenic systems (e.g. the Hedgehog system. A variety of sophisticated regulatory mechanisms interact to coordinate the overall level of cholesterol in cells, tissues and the entire organism. Accumulating evidence indicates that in additional to the more ‘traditional’ regulatory schemes, cholesterol homeostasis is also under the control of epigenetic mechanisms such as histone acetylation and DNA methylation. The available evidence supporting a role for these mechanisms in the control of cholesterol synthesis, elimination, transport and storage are the focus of this review.

  3. Epigenetic reprogramming in plant sexual reproduction.

    Science.gov (United States)

    Kawashima, Tomokazu; Berger, Frédéric

    2014-09-01

    Epigenetic reprogramming consists of global changes in DNA methylation and histone modifications. In mammals, epigenetic reprogramming is primarily associated with sexual reproduction and occurs during both gametogenesis and early embryonic development. Such reprogramming is crucial not only to maintain genomic integrity through silencing transposable elements but also to reset the silenced status of imprinted genes. In plants, observations of stable transgenerational inheritance of epialleles have argued against reprogramming. However, emerging evidence supports that epigenetic reprogramming indeed occurs during sexual reproduction in plants and that it has a major role in maintaining genome integrity and a potential contribution to epiallelic variation. PMID:25048170

  4. Epigenetic variation during the adult lifespan

    DEFF Research Database (Denmark)

    Talens, Rudolf P; Christensen, Kaare; Putter, Hein;

    2012-01-01

    The accumulation of epigenetic changes was proposed to contribute to the age-related increase in the risk of most common diseases. In this study on 230 monozygotic twin pairs (MZ pairs), aged 18-89 years, we investigated the occurrence of epigenetic changes over the adult lifespan. Using mass......-related increase in methylation variation was generally attributable to unique environmental factors, except for CRH, for which familial factors may play a more important role. In conclusion, sustained epigenetic differences arise from early adulthood to old age and contribute to an increasing discordance of MZ...

  5. Erwin Schroedinger, Francis Crick and epigenetic stability

    CERN Document Server

    Ogryzko, Vasily

    2007-01-01

    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 lead Schroedinger to promote the idea of molecular code-script for explanation of stability of biological order.

  6. Epigenetic reprogramming in mammalian nuclear transfer

    Institute of Scientific and Technical Information of China (English)

    LI Shijie; DU Weihua; LI Ning

    2004-01-01

    Somatic cloning has been succeeded in some species, but the cloning efficiency is very low, which limits the application of the technique in many areas of research and biotechnology. The cloning of mammals by somatic cell nuclear transfer (NT) requires epigenetic reprogramming of the differentiated state of donor cell to a totipotent, embryonic ground state. Accumulating evidence indicates that incomplete or inappropriate epigenetic reprogramming of donor nuclei is likely to be the primary cause of failures in nuclear transfer. This review summarizes the roles of various epigenetic mechanisms, including DNA methylation, histone acetylation, imprinting, X-chromosome inactivation, telomere maintenance and expressions of development-related genes on somatic nuclear transfer.

  7. Can the state of cancer chemotherapy resistance be reverted by epigenetic therapy?

    Directory of Open Access Journals (Sweden)

    Duenas-Gonzalez Alfonso

    2006-07-01

    Full Text Available Abstract Background Transcriptome analysis shows that the chemotherapy innate resistance state of tumors is characterized by: poorly dividing tumor cells; an increased DNA repair; an increased drug efflux potential by ABC-transporters; and a dysfunctional ECM. Because chemotherapy resistance involves multiple genes, epigenetic-mediated changes could be the main force responsible of this phenotype. Our hypothesis deals with the potential role of epigenetic therapy for affecting the chemotherapy resistant phenotype of malignant tumors. Presentation of the hypothesis Recent studies reveal the involvement of DNA methylation and histone modifications in the reprogramming of the genome of mammalian cells in cancer. In this sense, it can be hypothesized that epigenetic reprogramming can participate in the establishment of an epigenetic mark associated with the chemotherapy resistant phenotype. If this were correct, then it could be expected that agents targeting DNA methylation and histone deacetylation would by reverting the epigenetic mark induce a global expression profile that mirror the observed in untreated resistant cells. Testing the hypothesis It is proposed to perform a detailed analysis using all the available databases where the gene expression of primary tumors was analyzed and data correlated with the therapeutic outcome to determine whether a transcriptome profiling of "resistance" is observed. Assuming an epigenetic programming determines at some level the intrinsic resistant phenotype, then a similar pattern of gene expression dictated by an epigenetic mark should also be found in cell acquiring drug resistance. If these expectations are meet, then it should be further investigated at the genomic level whether these phenotypes are associated to certain patterns of DNA methylation and chromatin modification. Once confirmed the existence of an epigenetic mark associated to either the intrinsic or acquired chemotherapy resistant phenotype

  8. [Epigenetics of childhood obesity and diabetes].

    Science.gov (United States)

    Valladares-Salgado, Adán; Suárez-Sánchez, Fernando; Burguete-García, Ana I; Cruz, Miguel

    2014-01-01

    Obesity and type 2 diabetes mellitus (T2DM) result from sedentary lifestyle, high-carbohydrate diets and genetic predisposition. Epigenetics is a form of genetic regulation in specialized cells that does not involve changes in the deoxyribonucleic acid (DNA) sequence, but it can be inherited to one or more generations through mitosis or meiosis. Children whose mothers develop gestational diabetes are more likely to become obese and diabetic in adult life. DNA methylation is a major mechanism in the regulation of transcription and gene expression of several genes. High levels of glucose and insulin during pregnancy modify the risk of developing T2DM, suggesting that the expression pattern is modified due to cell memory in a specific tissue. If T2DM is linked to adaptation in utero, the obvious primary prevention is to protect the fetal development. Future epidemiological studies need to employ more accurate indicators or markers of development to show the relationship between a specific disease and the exposure to environmental factors. The mechanisms by which malnutrition, and intrauterine growth retardation produce changes in the metabolism of glucose and insuline are worth to explore in order to control obesity and T2DM. PMID:24866314

  9. Protection of melanized Cryptococcus neoformans from lethal dose gamma irradiation involves changes in melanin's chemical structure and paramagnetism.

    Directory of Open Access Journals (Sweden)

    Abdelahad Khajo

    Full Text Available Certain fungi thrive in highly radioactive environments including the defunct Chernobyl nuclear reactor. Cryptococcus neoformans (C. neoformans, which uses L-3,4-dihydroxyphenylalanine (L-DOPA to produce melanin, was used here to investigate how gamma radiation under aqueous aerobic conditions affects the properties of melanin, with the aim of gaining insight into its radioprotective role. Exposure of melanized fungal cell in aqueous suspensions to doses of γ-radiation capable of killing 50 to 80% of the cells did not lead to a detectable loss of melanin integrity according to EPR spectra of melanin radicals. Moreover, upon UV-visible (Xe-lamp illumination of melanized cells, the increase in radical population was unchanged after γ-irradiation. Gamma-irradiation of frozen cell suspensions and storage of samples for several days at 77 K however, produced melanin modification noted by a reduced radical population and reduced photoresponse. More direct evidence for structural modification of melanin came from the detection of soluble products with absorbance maxima near 260 nm in supernatants collected after γ-irradiation of cells and cell-free melanin. These products, which include thiobarbituric acid (TBA-reactive aldehydes, were also generated by Fenton reagent treatment of cells and cell-free melanin. In an assay of melanin integrity based on the metal (Bi(+3 binding capacity of cells, no detectable loss in binding was detected after γ-irradiation. Our results show that melanin in C. neoformans cells is susceptible to some damage by hydroxyl radical formed in lethal radioactive aqueous environments and serves a protective role in melanized fungi that involves sacrificial breakdown.

  10. Long-term epigenetic alterations in a rat model of Gulf War Illness.

    Science.gov (United States)

    Pierce, Lisa M; Kurata, Wendy E; Matsumoto, Karen W; Clark, Margaret E; Farmer, Douglas M

    2016-07-01

    Gulf War Illness (GWI) is a chronic, multisymptom illness that affects 25% of the 700,000 US veterans deployed to the Persian Gulf during the 1990-1991 Gulf War. Central nervous system impairments are among the most common symptoms reported, including memory dysfunction and depression. After 25 years, the diagnosis remains elusive, useful treatments are lacking, and the cause is poorly understood, although exposures to pyridostigmine bromide (PB) and pesticides are consistently identified to be among the strongest risk factors. Epigenetic changes including altered microRNA (miRNA) expression and DNA methylation play an important role in learning, memory, and emotion regulation and have been implicated in various neurological disorders. In this study, we used an established rat model of GWI to determine whether 1) chronic alterations in miRNA expression and global DNA methylation and DNA hydroxymethylation are mechanisms involved in the pathobiology of GWI, and 2) plasma exosome small RNAs may serve as potential noninvasive biomarkers of this debilitating disease. One year after a 28-day exposure regimen of PB, DEET (N,N-diethyl-3-methylbenzamide), permethrin, and mild stress, expression of 84 mature miRNAs and global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) content were analyzed in the brains of GWI rats and vehicle controls by PCR array and enzyme-linked immunosorbent assay, respectively. Plasma exosome RNA next-generation sequencing analysis was performed in pooled samples to discover potential noninvasive biomarkers. We found that combined exposure to low doses of GW-related chemicals and mild stress caused epigenetic modifications in the brain that persisted one year after exposure, including increased expression of miR-124-3p and miR-29b-3p in the hippocampus and regional alterations in global 5mC and 5hmC content. GW-relevant exposures also induced the differential expression of two piwi-interacting RNAs (piRNAs) in circulation (piR-007899

  11. 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......, development and maintenance of tissue-specific gene expression. These mechanisms also explain how cells with the same DNA content can differentiate into cells with different functions. Changes in epigenetic processes can lead to changes in gene function, cancer formation and progression, as well as other...

  12. 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....

  13. 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. PMID:18243109

  14. Clinical significance of the interaction between non-coding RNAs and the epigenetics machinery: Challenges and opportunities in oncology

    OpenAIRE

    Maia, Beatriz M; Rocha, Rafael M; CALIN, GEORGE A.

    2013-01-01

    Non-coding RNAs and epigenetics are remarkable mechanisms of cellular control. In this review we underline the processes by which non-coding RNAs (ncRNAs), shown to be involved in various diseases, are capable of modifying and being modified by the epigenetic machinery, emphasizing the clinical importance of this network in cancer. Many ncRNAs have been described that play important roles in the establishment and maintenance of the epigenome. However, only a few studies deeply take into accou...

  15. From Neo-Darwinism to Epigenetic Inheritance

    OpenAIRE

    Axholm, Ida; Ranum, Kasper; Al-Makdisi Razeeghi, Redaa

    2014-01-01

    Transgenerational epigenetic inheritance is at variance with the neo-Darwinian theory of inheritance, and this possibly has important implications for how we view evolution, since it could allow for a kind of inheritance of acquired characteristics. We have applied Imre Lakatos and Thomas Kuhn’s models of scientific change and investigated if they can accurately describe the change in the view on inheritance from neo-Darwinism to a view that includes transgenerational epigenetic inheritance, ...

  16. Epigenetic Mechanisms of Facioscapulohumeral Muscular Dystrophy

    OpenAIRE

    de Greef, Jessica C; Frants, Rune R; van der Maarel, Silvère M.

    2008-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) seems to be caused by a complex epigenetic disease mechanism as a result of contraction of the polymorphic macrosatellite repeat D4Z4 on chromosome 4qter. Currently, the exact mechanism causing the FSHD phenotype is still not elucidated. In this review, we discuss the genetic and epigenetic changes observed in patients with FSHD and the possible disease mechanisms that may be associated with FSHD pathogenesis.

  17. Host epigenetic modifications by oncogenic viruses

    OpenAIRE

    Flanagan, J. M.

    2006-01-01

    Epigenetic alterations represent an important step in the initiation and progression of most human cancers, but it is difficult to differentiate the early cancer causing alterations from later consequences. Oncogenic viruses can induce transformation via expression of only a small number of viral genes. Therefore, the mechanisms by which oncogenic viruses cause cancer may provide clues as to which epigenetic alterations are critical in early carcinogenesis.

  18. Environmental stress and epigenetic transgenerational inheritance

    OpenAIRE

    Skinner, Michael K.

    2014-01-01

    Previous studies have shown a wide variety of environmental toxicants and abnormal nutrition can promote the epigenetic transgenerational inheritance of disease. More recently a number of studies have indicated environmental stress can also promote epigenetic alterations that are transmitted to subsequent generations to induce pathologies. A recent study by Yao and colleagues demonstrated gestational exposure to restraint stress and forced swimming promoted preterm birth risk and adverse newb...

  19. Epigenetics, society, and bio-objects

    OpenAIRE

    Svalastog, Anna Lydia; Damjanovicova, Maria

    2015-01-01

    The molecular account of the environmental that epigenetics offers bestow it with paramount importance for biomedical perspective of health and disease and for social sciences perspective on human interactions and well-being. It offers new prospects for interventions to shape the health of both individuals and populations, and invokes its own ethical, legal, and social implications. We here propose treatment of the relation between epigenetics and society through the framework of bio-objectif...

  20. Orchestrating epigenetic roles targeting ocular tumors

    OpenAIRE

    Wen X; Lu L; Zhang H.; Fan X

    2016-01-01

    Xuyang Wen*, Linna Lu*, He Zhang, Xianqun Fan Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Epigenetics is currently one of the most promising areas of study in the field of biomedical research. Scientists have dedicated their efforts to studying epigenetic mechanisms in cancer for centuries. Additionally, the ...

  1. Epigenetic influences on the developing brain: effects of hormones and nutrition

    Directory of Open Access Journals (Sweden)

    Nugent BM

    2015-05-01

    Full Text Available Bridget M Nugent,1 Margaret M McCarthy2 1Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA Abstract: The developing brain is subject to modifying influences, both in utero and early postnatally. Some of these are intrinsic, such as gonadal steroids, while others are externally imposed, such as maternal nutrition or stress. All of these variables can have enduring consequences by imposing epigenetic modifications on the genome that alter set points for activation in adulthood, thereby reflecting early-life programming. In this review, we provide an overview of the most well studied epigenetic processes that occur in the brain. Next, we summarize the studies to date that have implicated gonadal steroids, stress exposure, and nutritional deficits/excess in changes in neural epigenetic marks, which ultimately alter brain development, but we also note that this field is still in its infancy. Epigenetic regulators include DNA methylation, changes to the chromatin via acetylation and other chemical modifiers, and noncoding RNAs all of which impact the expression of specific genes. In this way gonadal steroids in the developing male fetus direct masculinization of adult brain and behavior, and similarly in utero exposure to a high-fat or calorie-restricted diet impacts glucose metabolism and body fat composition throughout life. Stress early in life changes the sensitivity of the hypothalamic–pituitary–adrenal (HPA axis to subsequent stressors and this too is mediated, at least in part, by epigenetic changes to key genes to alter the responsiveness threshold. Epigenetics is the integration of the environment and the genome, and hormones and nutrition provide the bridge that allows that integration to occur. Keywords: epigenetics, early-life programming, brain development, hormones, nutrition 

  2. 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.

  3. Epigenetic regulation of hematopoietic stem cell aging

    International Nuclear Information System (INIS)

    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

  4. TALEored Epigenetics: A DNA-Binding Scaffold for Programmable Epigenome Editing and Analysis.

    Science.gov (United States)

    Kubik, Grzegorz; Summerer, Daniel

    2016-06-01

    Epigenetic modification of the cytosine 5-position is an important regulator of gene expression with essential roles in genome stability, development, and disease. In addition to 5-methylcytosine (mC), the oxidized mC derivatives 5-hydroxymethyl-, 5-formyl-, and 5-carboxylcytosine (hmC, fC, and caC) have recently been discovered. These are intermediates of an active demethylation pathway but might also represent new epigenetic marks with individual biological roles. This increase in chemical complexity of DNA-encoded information has created a pressing need for new approaches that allow reading and editing of this information. Transcription-activator-like effectors (TALEs) are DNA-binding domains with programmable sequence selectivity that enable the direct reading of epigenetic cytosine modifications but can also guide enzymatic editing domains to genomic loci of choice. Here, we review recent advances in employing TALEs for these applications. PMID:26972580

  5. Radiation-induced epigenetic alterations after low and high LET irradiations

    Energy Technology Data Exchange (ETDEWEB)

    Aypar, Umut, E-mail: uaypa001@umaryland.edu [Department of Radiation Oncology, Radiation Oncology Research Laboratory, University of Maryland School of Medicine, Baltimore, MD 21201 (United States); Morgan, William F. [Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Baulch, Janet E. [Department of Radiation Oncology, Radiation Oncology Research Laboratory, University of Maryland School of Medicine, Baltimore, MD 21201 (United States)

    2011-02-10

    Epigenetics, including DNA methylation and microRNA (miRNA) expression, could be the missing link in understanding radiation-induced genomic instability (RIGI). This study tests the hypothesis that irradiation induces epigenetic aberrations, which could eventually lead to RIGI, and that the epigenetic aberrations induced by low linear energy transfer (LET) irradiation are different than those induced by high LET irradiations. GM10115 cells were irradiated with low LET X-rays and high LET iron (Fe) ions and evaluated for DNA damage, cell survival and chromosomal instability. The cells were also evaluated for specific locus methylation of nuclear factor-kappa B (NF{kappa}B), tumor suppressor in lung cancer 1 (TSLC1) and cadherin 1 (CDH1) gene promoter regions, long interspersed nuclear element 1 (LINE-1) and Alu repeat element methylation, CpG and non-CpG global methylation and miRNA expression levels. Irradiated cells showed increased micronucleus induction and cell killing immediately following exposure, but were chromosomally stable at delayed times post-irradiation. At this same delayed time, alterations in repeat element and global DNA methylation and miRNA expression were observed. Analyses of DNA methylation predominantly showed hypomethylation, however hypermethylation was also observed. We demonstrate that miRNA expression levels can be altered after X-ray irradiation and that these miRNA are involved in chromatin remodeling and DNA methylation. A higher incidence of epigenetic changes was observed after exposure to X-rays than Fe ions even though Fe ions elicited more chromosomal damage and cell killing. This distinction is apparent at miRNA analyses at which only three miRNA involved in two major pathways were altered after high LET irradiations while six miRNA involved in five major pathways were altered after low LET irradiations. This study also shows that the irradiated cells acquire epigenetic changes suggesting that epigenetic aberrations may arise

  6. Radiation-induced epigenetic alterations after low and high LET irradiations

    International Nuclear Information System (INIS)

    Epigenetics, including DNA methylation and microRNA (miRNA) expression, could be the missing link in understanding radiation-induced genomic instability (RIGI). This study tests the hypothesis that irradiation induces epigenetic aberrations, which could eventually lead to RIGI, and that the epigenetic aberrations induced by low linear energy transfer (LET) irradiation are different than those induced by high LET irradiations. GM10115 cells were irradiated with low LET X-rays and high LET iron (Fe) ions and evaluated for DNA damage, cell survival and chromosomal instability. The cells were also evaluated for specific locus methylation of nuclear factor-kappa B (NFκB), tumor suppressor in lung cancer 1 (TSLC1) and cadherin 1 (CDH1) gene promoter regions, long interspersed nuclear element 1 (LINE-1) and Alu repeat element methylation, CpG and non-CpG global methylation and miRNA expression levels. Irradiated cells showed increased micronucleus induction and cell killing immediately following exposure, but were chromosomally stable at delayed times post-irradiation. At this same delayed time, alterations in repeat element and global DNA methylation and miRNA expression were observed. Analyses of DNA methylation predominantly showed hypomethylation, however hypermethylation was also observed. We demonstrate that miRNA expression levels can be altered after X-ray irradiation and that these miRNA are involved in chromatin remodeling and DNA methylation. A higher incidence of epigenetic changes was observed after exposure to X-rays than Fe ions even though Fe ions elicited more chromosomal damage and cell killing. This distinction is apparent at miRNA analyses at which only three miRNA involved in two major pathways were altered after high LET irradiations while six miRNA involved in five major pathways were altered after low LET irradiations. This study also shows that the irradiated cells acquire epigenetic changes suggesting that epigenetic aberrations may arise in the

  7. Epigenetic approaches towards radiation countermeasure

    International Nuclear Information System (INIS)

    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)

  8. Gut indigenous microbiota and epigenetics

    Directory of Open Access Journals (Sweden)

    Boris Arkadievich Shenderov

    2012-03-01

    Full Text Available This review introduces and discusses data regarding fundamental and applied investigations in mammalian epigenomics and gut microbiota received over the last 10 years. Analysis of these data enabled the author first to come to the conclusion that the multiple low molecular weight substances of indigenous gut microbiota origin should be considered one of the main endogenous factors actively participating in epigenomic mechanisms that responsible for the mammalian genome reprogramming and post-translated modifications. Gut microecological imbalance coursed by various biogenic and abiogenic agents and factors can produce the different epigenetic abnormalities and the onset and progression of metabolic diseases associated. The author substantiates the necessity to create an international project ‘Human Gut Microbiota and Epigenomics’ that facilitates interdisciplinary collaborations among scientists and clinicians engaged in host microbial ecology, nutrition, metagenomics, epigenomics and metabolomics investigations as well as in diseases prevention and treatment. Some priority scientific and applied directions in the current omic technologies coupled with gnotobiological approaches are suggested that can open a new era in characterizing the role of the symbiotic microbiota small metabolic and signal molecules in the host epigenomics. Although discussed subject is only at an early stage its validation can open novel approaches in drug discovery studies.

  9. 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…

  10. The histone variant macroH2A is an epigenetic regulator of key developmental genes

    DEFF Research Database (Denmark)

    Buschbeck, Marcus; Uribesalgo, Iris; Wibowo, Indra; Rué, Pau; Martin, David; Gutierrez, Arantxa; Morey, Lluís; Guigó, Roderic; López-Schier, Hernán; Di Croce, Luciano

    2009-01-01

    activation of HOXA cluster genes during neuronal differentiation. Furthermore, elimination of macroH2A2 function in zebrafish embryos produced severe but specific phenotypes. Taken together, our data demonstrate that macroH2A variants constitute an important epigenetic mark involved in the concerted...

  11. Epigenetic Regulation of Inflammatory Cytokines and Associated Genes in Human Malignancies

    OpenAIRE

    Rehana Yasmin; Sami Siraj; Amjad Hassan; Abdul Rehman Khan; Rashda Abbasi; Nafees Ahmad

    2015-01-01

    Inflammation is a multifaceted defense response of immune system against infection. Chronic inflammation has been implicated as an imminent threat for major human malignancies and is directly linked to various steps involved in tumorigenesis. Inflammatory cytokines, interleukins, interferons, transforming growth factors, chemokines, and adhesion molecules have been associated with chronic inflammation. Numerous cytokines are reported to be aberrantly regulated by different epigenetic mechanis...

  12. Epigenetic regulation of extracellular-superoxide dismutase in human monocytes.

    Science.gov (United States)

    Kamiya, Tetsuro; Machiura, Masatomo; Makino, Junya; Hara, Hirokazu; Hozumi, Isao; Adachi, Tetsuo

    2013-08-01

    Extracellular-superoxide dismutase (EC-SOD) is a major SOD isozyme mainly present in the vascular wall and plays an important role in normal redox homeostasis. We previously showed the significant reduction or induction of EC-SOD during human monocytic U937 or THP-1 cell differentiation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), respectively; however, its cell-specific expression and regulation have not been fully elucidated. It has been reported that epigenetic factors, such as DNA methylation and histone modification, are involved in several kinds of gene regulation. In this study, we investigated the involvement of epigenetic factors in EC-SOD expression and determined high levels of DNA methylation within promoter and coding regions of EC-SOD in THP-1 cells compared to those in U937 cells. Moreover, treatment with a DNA methyltransferase inhibitor, 5-azacytidine, significantly induced the expression of EC-SOD in THP-1 cells, indicating the importance of DNA methylation in the suppression of EC-SOD expression; however, the DNA methylation status did not change during THP-1 cell differentiation induced by TPA. On the other hand, we detected histone H3 and H4 acetylation during differentiation. Further, pretreatment with histone acetyltransferase inhibitors, CPTH2 or garcinol, significantly suppressed the TPA-inducible EC-SOD expression. We also determined the epigenetic suppression of EC-SOD in peripheral blood mononuclear cells. Treatment with granulocyte macrophage colony-stimulating factor (GM-CSF)/granulocyte-CSF induced that expression. Overall, these findings provide novel evidence that cell-specific and TPA-inducible EC-SOD expression are regulated by DNA methylation and histone H3 and H4 acetylation in human monocytic cells. PMID:23602908

  13. Molecular Modeling and Chemoinformatics to Advance the Development of Modulators of Epigenetic Targets: A Focus on DNA Methyltransferases.

    Science.gov (United States)

    Prieto-Martínez, F D; Peña-Castillo, A; Méndez-Lucio, O; Fernández-de Gortari, E; Medina-Franco, J L

    2016-01-01

    In light of the emerging field of Epi-informatics, ie, computational methods applied to epigenetic research, molecular docking, and dynamics, pharmacophore and activity landscape modeling and QSAR play a key role in the development of modulators of DNA methyltransferases (DNMTs), one of the major epigenetic target families. The increased chemical information available for modulators of DNMTs has opened up the avenue to explore the epigenetic relevant chemical space (ERCS). Herein, we discuss recent progress on the identification and development of inhibitors of DNMTs as potential epi-drugs and epi-probes that have been driven by molecular modeling and chemoinformatics methods. We also survey advances on the elucidation of their structure-activity relationships and exploration of ERCS. Finally, it is illustrated how computational approaches can be applied to identify modulators of DNMTs in food chemicals. PMID:27567482

  14. The Role of Epigenetics in Resistance to Cisplatin Chemotherapy in Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    O' Byrne, Kenneth J.; Barr, Martin P.; Gray, Steven G., E-mail: sgray@stjames.ie [Trinity College Dublin, Department of Clinical Medicine, Trinity Centre for Health Sciences, St James Hospital, James Street, Dublin 8 (Ireland)

    2011-03-17

    Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20–30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC.

  15. Fetal programming of Parkinson’s and Alzheimer’s diseases: the role of epigenetic factors

    Directory of Open Access Journals (Sweden)

    Monica Piras

    2014-06-01

    Full Text Available In this paper, the main epigenetic factors involved in shaping the brain’s physical structure during development will be reviewed, with special emphasis on those related to Parkinson’s disease and Alzheimer’s disease in adulthood. These factors are: preterm delivery, maternal diet, trace metals, intrauterine infection, maternal stress, drugs, alcohol. Epigenetics may allow a novel therapeutic and preventive approach for neurodegeneration. Proceedings of the 10th International Workshop on Neonatology · Cagliari (Italy · October 22nd-25th, 2014 · The last ten years, the next ten years in Neonatology Guest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgiou

  16. Public health risks associated with oil and chemical spills in cold freshwater environments: a simulation exercise involving a phenol and diesel spill in the St. Lawrence River

    International Nuclear Information System (INIS)

    The St. Lawrence River is the source of drinking water for some 45 per cent of the population in the Province of Quebec, hence contamination of the river by oil or chemical spills is a matter of great public health importance. Project SHORES was developed by the Quebec Environmental Health Committee through the St. Lawrence 'Vision 2000' Action Plan. As part of this project, a simulation exercise involving phenol and diesel fuel was carried out. The exercise included development of a computerized dispersion model which was then used to evaluate the migration of phenol in critical areas of the St. Lawrence River. Main public health risks to nearby populations, with emphasis on drinking water contamination, were assessed based on the simulation results. 18 refs., 2 tabs. 1 fig

  17. Integrated analysis of genome-wide genetic and epigenetic association data for identification of disease mechanisms.

    Science.gov (United States)

    Ke, Xiayi; Cortina-Borja, Mario; Silva, Bruno Cesar; Lowe, Robert; Rakyan, Vardhman; Balding, David

    2013-11-01

    Many human diseases are multifactorial, involving multiple genetic and environmental factors impacting on one or more biological pathways. Much of the environmental effect is believed to be mediated through epigenetic changes. Although many genome-wide genetic and epigenetic association studies have been conducted for different diseases and traits, it is still far from clear to what extent the genomic loci and biological pathways identified in the genetic and epigenetic studies are shared. There is also a lack of statistical tools to assess these important aspects of disease mechanisms. In the present study, we describe a protocol for the integrated analysis of genome-wide genetic and epigenetic data based on permutation of a sum statistic for the combined effects in a locus or pathway. The method was then applied to published type 1 diabetes (T1D) genome-wide- and epigenome-wide-association studies data to identify genomic loci and biological pathways that are associated with T1D genetically and epigenetically. Through combined analysis, novel loci and pathways were also identified, which could add to our understanding of disease mechanisms of T1D as well as complex diseases in general. PMID:24071862

  18. Epigenetic regulation leading to induced pluripotency drives cancer development in vivo

    International Nuclear Information System (INIS)

    Highlights: • Epigenetic regulation of failed reprogramming-associated cancer cells is discussed. • Similarity between pediatric cancer and reprogramming-associated cancer is discussed. • Concept for epigenetic cancer is discussed. - Abstract: Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by the transient expression of reprogramming factors. During the reprogramming process, somatic cells acquire the ability to undergo unlimited proliferation, which is also an important characteristic of cancer cells, while their underlying DNA sequence remains unchanged. Based on the characteristics shared between pluripotent stem cells and cancer cells, the potential involvement of the factors leading to reprogramming toward pluripotency in cancer development has been discussed. Recent in vivo reprogramming studies provided some clues to understanding the role of reprogramming-related epigenetic regulation in cancer development. It was shown that premature termination of the in vivo reprogramming result in the development of tumors that resemble pediatric cancers. Given that epigenetic modifications play a central role during reprogramming, failed reprogramming-associated cancer development may have provided a proof of concept for epigenetics-driven cancer development in vivo

  19. Epigenetic regulation leading to induced pluripotency drives cancer development in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Ohnishi, Kotaro [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507 (Japan); Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194 (Japan); Semi, Katsunori [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507 (Japan); Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507 (Japan); Yamada, Yasuhiro, E-mail: y-yamada@cira.kyoto-u.ac.jp [Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507 (Japan); Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507 (Japan)

    2014-12-05

    Highlights: • Epigenetic regulation of failed reprogramming-associated cancer cells is discussed. • Similarity between pediatric cancer and reprogramming-associated cancer is discussed. • Concept for epigenetic cancer is discussed. - Abstract: Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by the transient expression of reprogramming factors. During the reprogramming process, somatic cells acquire the ability to undergo unlimited proliferation, which is also an important characteristic of cancer cells, while their underlying DNA sequence remains unchanged. Based on the characteristics shared between pluripotent stem cells and cancer cells, the potential involvement of the factors leading to reprogramming toward pluripotency in cancer development has been discussed. Recent in vivo reprogramming studies provided some clues to understanding the role of reprogramming-related epigenetic regulation in cancer development. It was shown that premature termination of the in vivo reprogramming result in the development of tumors that resemble pediatric cancers. Given that epigenetic modifications play a central role during reprogramming, failed reprogramming-associated cancer development may have provided a proof of concept for epigenetics-driven cancer development in vivo.

  20. Genetic and epigenetic mechanisms of regulation, chronology and dynamics of spermatogenesis of mammals

    Directory of Open Access Journals (Sweden)

    L. F. Kurilo

    2015-01-01

    Full Text Available Genetic and epigenetic mechanisms of spermatogenesis – long process with many stages regulation are discussed. DNA code is the entirety of hereditary information, epigenetic mechanisms of gene regulation act without altering primary nucleotide sequences. Epigenetic regulation is a complex process, in which components of different groups of epigenetic modifications (non-coding RNAs, DNA methylation and histone modification work together. Mistakes in any of the components of the process may cause impaired spermatogenesis and/or infertility, and may cause epigenetic diseases. Nowadays 90 imprinted genes and loci on 13 chromosomes are revealed. More then 10 human diseases involving genomic imprinting are known (Angelman syndrome, Prader–Willi syndrome, Russell–Silver syndrome, Beckwith–Wiedemann syndrome etc.. DNA methylation is essential for normal development and is associated with a number of key processes including animal growth and development, transcription, DNA replication and reparation, cell differentiation, genomic imprinting, X-chromosome inactivation, suppression of repetitive elements and carcinogenesis. 

  1. Genetic and epigenetic mechanisms of regulation, chronology and dynamics of spermatogenesis of mammals

    Directory of Open Access Journals (Sweden)

    L. F. Kurilo

    2015-04-01

    Full Text Available Genetic and epigenetic mechanisms of spermatogenesis – long process with many stages regulation are discussed. DNA code is the entirety of hereditary information, epigenetic mechanisms of gene regulation act without altering primary nucleotide sequences. Epigenetic regulation is a complex process, in which components of different groups of epigenetic modifications (non-coding RNAs, DNA methylation and histone modification work together. Mistakes in any of the components of the process may cause impaired spermatogenesis and/or infertility, and may cause epigenetic diseases. Nowadays 90 imprinted genes and loci on 13 chromosomes are revealed. More then 10 human diseases involving genomic imprinting are known (Angelman syndrome, Prader–Willi syndrome, Russell–Silver syndrome, Beckwith–Wiedemann syndrome etc.. DNA methylation is essential for normal development and is associated with a number of key processes including animal growth and development, transcription, DNA replication and reparation, cell differentiation, genomic imprinting, X-chromosome inactivation, suppression of repetitive elements and carcinogenesis. 

  2. Natural Killer Cells—An Epigenetic Perspective of Development and Regulation

    Directory of Open Access Journals (Sweden)

    Alexander Schenk

    2016-03-01

    Full Text Available Based on their ability to recognize and eliminate various endo- and exogenous pathogens as well as pathological alterations, Natural Killer (NK cells represent an important part of the cellular innate immune system. Although the knowledge about their function is growing, little is known about their development and regulation on the molecular level. Research of the past decade suggests that modifications of the chromatin, which do not affect the base sequence of the DNA, also known as epigenetic alterations, are strongly involved in these processes. Here, the impact of epigenetic modifications on the development as well as the expression of important activating and inhibiting NK-cell receptors and their effector function is reviewed. Furthermore, external stimuli such as physical activity and their influence on the epigenetic level are discussed.

  3. Natural Killer Cells—An Epigenetic Perspective of Development and Regulation

    Science.gov (United States)

    Schenk, Alexander; Bloch, Wilhelm; Zimmer, Philipp

    2016-01-01

    Based on their ability to recognize and eliminate various endo- and exogenous pathogens as well as pathological alterations, Natural Killer (NK) cells represent an important part of the cellular innate immune system. Although the knowledge about their function is growing, little is known about their development and regulation on the molecular level. Research of the past decade suggests that modifications of the chromatin, which do not affect the base sequence of the DNA, also known as epigenetic alterations, are strongly involved in these processes. Here, the impact of epigenetic modifications on the development as well as the expression of important activating and inhibiting NK-cell receptors and their effector function is reviewed. Furthermore, external stimuli such as physical activity and their influence on the epigenetic level are discussed. PMID:26938533

  4. Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation.

    Science.gov (United States)

    Chen, Kelan; Hu, Jiang; Moore, Darcy L; Liu, Ruijie; Kessans, Sarah A; Breslin, Kelsey; Lucet, Isabelle S; Keniry, Andrew; Leong, Huei San; Parish, Clare L; Hilton, Douglas J; Lemmers, Richard J L F; van der Maarel, Silvère M; Czabotar, Peter E; Dobson, Renwick C J; Ritchie, Matthew E; Kay, Graham F; Murphy, James M; Blewitt, Marnie E

    2015-07-01

    Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic repressor with described roles in X inactivation and genomic imprinting, but Smchd1 is also critically involved in the pathogenesis of facioscapulohumeral dystrophy. The underlying molecular mechanism by which Smchd1 functions in these instances remains unknown. Our genome-wide transcriptional and epigenetic analyses show that Smchd1 binds cis-regulatory elements, many of which coincide with CCCTC-binding factor (Ctcf) binding sites, for example, the clustered protocadherin (Pcdh) genes, where we show Smchd1 and Ctcf act in opposing ways. We provide biochemical and biophysical evidence that Smchd1-chromatin interactions are established through the homodimeric hinge domain of Smchd1 and, intriguingly, that the hinge domain also has the capacity to bind DNA and RNA. Our results suggest Smchd1 imparts epigenetic regulation via physical association with chromatin, which may antagonize Ctcf-facilitated chromatin interactions, resulting in coordinated transcriptional control. PMID:26091879

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

    International Nuclear Information System (INIS)

    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)

  6. Epigenetic biomarkers in esophageal cancer.

    Science.gov (United States)

    Kaz, Andrew M; Grady, William M

    2014-01-28

    The aberrant DNA methylation of tumor suppressor genes is well documented in esophageal cancer, including adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) as well as in Barrett's esophagus (BE), a pre-malignant condition that is associated with chronic acid reflux. BE is a well-recognized risk factor for the development of EAC, and consequently the standard of care is for individuals with BE to be placed in endoscopic surveillance programs aimed at detecting early histologic changes that associate with an increased risk of developing EAC. Yet because the absolute risk of EAC in individuals with BE is minimal, a clinical need in the management of BE is the identification of additional risk markers that will indicate individuals who are at a significant absolute risk of EAC so that they may be subjected to more intensive surveillance. The best currently available risk marker is the degree of dysplasia in endoscopic biopsies from the esophagus; however, this marker is suboptimal for a variety of reasons. To date, there are no molecular biomarkers that have been translated to widespread clinical practice. The search for biomarkers, including hypermethylated genes, for either the diagnosis of BE, EAC, or ESCC or for risk stratification for the development of EAC in those with BE is currently an area of active research. In this review, we summarize the status of identified candidate epigenetic biomarkers for BE, EAC, and ESCC. Most of these aberrantly methylated genes have been described in the context of early detection or diagnostic markers; others might prove useful for estimating prognosis or predicting response to treatment. Finally, special attention will be paid to some of the challenges that must be overcome in order to develop clinically useful esophageal cancer biomarkers. PMID:22406828

  7. Epigenetic mechanism of radiation carcinogenesis

    International Nuclear Information System (INIS)

    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 mechanism of radiation carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Niwa, Ohtsura [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine

    1995-12-01

    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)

  9. Epigenetic mechanisms of Rubinstein-Taybi syndrome.

    Science.gov (United States)

    Park, Elizabeth; Kim, Yunha; Ryu, Hyun; Kowall, Neil W; Lee, Junghee; Ryu, Hoon

    2014-03-01

    Rubinstein-Taybi syndrome (RTS) is an incurable genetic disorder with combination of mental retardation and physical features including broad thumbs and toes, craniofacial abnormalities, and growth deficiency. While the autosomal dominant mode of transmission is limitedly known, the majority of cases are attributable to de novo mutations in RTS. The first identified gene associated with RTS is CREB-binding protein (CREBBP/CBP). Alterations of the epigenetic 'histone code' due to dysfunction of the CBP histone acetyltransferase activity deregulate gene transcriptions that are prominently linked to RTS pathogenesis. In this review, we discuss how CBP mutation contributes to modifications of histone and how histone deacetylase inhibitors are therapeutically applicable to epigenetic conditioning in RTS. Since most genetic mutations are irreversible and therapeutic approaches are limited, therapeutic targeting of reversible epigenetic components altered in RTS may be an ideal strategy. Expeditious further study on the role of the epigenetic mechanisms in RTS is encouraged to identify novel epigenetic markers and therapeutic targets to treat RTS. PMID:24381114

  10. A special issue on ‘epigenetics'

    Institute of Scientific and Technical Information of China (English)

    Wenlin Xu; Minghua Xu

    2012-01-01

    The term epigenetics was coined by Waddington CH in 1940s as a portmanteau of the words genetics and epigenesis to describe the differentiation of cells from their initial totipotent state in embryonic development.With the explosion of knowledge in this field in the recent 10 years,epigenetics is now typically defined as the study of heritable changes in gene expression that are not due to changes in the nucleotide sequence of DNA.The field of epigenetics is revolutionizing our understanding of biology and medicine.Recent studies have been focusing on the mechanisms of epigenetic regulation,including DNA methylation, histone modification,chromatin remodeling,etc.,and on their contributions to development and diseases.In this special issue,nine review articles written by prominent experts in this field are put together,trying to give our readers a broad picture of epigenetics and a summary of most recent research progress in this field.Here is a preview of what you will find in this issue.

  11. Epigenetic Mechanisms of Rubinstein-Taybi Syndrome

    Science.gov (United States)

    Park, Elizabeth; Kim, Yunha; Ryu, Hyun; Kowall, Neil W.; Lee, Junghee; Ryu, Hoon

    2014-01-01

    Rubinstein-Taybi Syndrome (RTS) is an incurable genetic disorder with combination of mental retardation and physical features including broad thumbs and toes, craniofacial abnormalities, and growth deficiency. While the autosomal dominant mode of transmission is limitedly known, the majority of cases are attributable to de novo mutations in RTS. The first identified gene associated with RTS is CREB-binding protein (CREBBP/CBP). Alterations of the epigenetic ‘histone code’ due to dysfunction of the CBP histone acetyltransferase (HAT) activity deregulates gene transcription that are prominently linked to RTS pathogenesis. In this review, we discuss how CBP mutation contributes to modifications of histone and how HDAC inhibitors are therapeutically applicable to epigenetic conditioning in RTS. Since most genetic mutations are irreversible and therapeutic approaches are limited, therapeutic targeting of reversible epigenetic components altered in RTS may be an ideal strategy. Expeditious further study on the role of the epigenetic mechanisms in RTS is encouraged to identify novel epigenetic biological markers and therapeutic targets to treat RTS. PMID:24381114

  12. Transposable element origins of epigenetic gene regulation.

    Science.gov (United States)

    Lisch, Damon; Bennetzen, Jeffrey L

    2011-04-01

    Transposable elements (TEs) are massively abundant and unstable in all plant genomes, but are mostly silent because of epigenetic suppression. Because all known epigenetic pathways act on all TEs, it is likely that the specialized epigenetic regulation of regular host genes (RHGs) was co-opted from this ubiquitous need for the silencing of TEs and viruses. With their internally repetitive and rearranging structures, and the acquisition of fragments of RHGs, the expression of TEs commonly makes antisense RNAs for both TE genes and RHGs. These antisense RNAs, particularly from heterochromatic reservoirs of 'zombie' TEs that are rearranged to form variously internally repetitive structures, may be advantageous because their induction will help rapidly suppress active TEs of the same family. RHG fragments within rapidly rearranging TEs may also provide the raw material for the ongoing generation of miRNA genes. TE gene expression is regulated by both environmental and developmental signals, and insertions can place nearby RHGs under the regulation (both standard and epigenetic) of the TE. The ubiquity of TEs, their frequent preferential association with RHGs, and their ability to be programmed by epigenetic signals all indicate that RGHs have nearly unlimited access to novel regulatory cassettes to assist plant adaptation. PMID:21444239

  13. Pediatric neuroblastomas: genetic and epigenetic 'danse macabre'.

    Science.gov (United States)

    van Noesel, Max M; Versteeg, Rogier

    2004-01-21

    Neuroblastomas are the most frequently occurring solid tumors in children under 5 years. Spontaneous regression is more common in neuroblastomas than in any other tumor type, especially in young patients under 12 months. Unfortunately, the full clinical spectrum of neuroblastomas also includes very aggressive tumors, unresponsive to multi-modality treatment and accounting for most of the pediatric cancer mortalities under 5 years of age. It is generally emphasized that more than one biological entity of neuroblastoma exists. Structural genetic defects such as amplification of MYCN, gain of chromosome 17q and LOH of 1p and several other chromosomal regions have proven to be valuable as prognostic factors and will be discussed in relation to their clinical relevance. Recent research is starting to uncover important molecular pathways involved in the pathogenesis of neuroblastomas. The aim of this review is to discuss several important aspects of the biology of the neuroblast, such as the role of overexpressed oncogenes like MYCN and cyclin D1, the mechanisms leading to decreased apoptosis, like overexpression of BCL-2, survivin, NM23, epigenetic silencing of caspase 8 and the role of tumor suppressor genes, like p53, p73 and RASSF1A. In addition, the role of specific proteins overexpressed in neuroblastomas, such as the neurotrophin receptors TrkA, B and C in relation to spontaneous regression and anti-angiogenesis will be discussed. Finally, we will try to relate these pathways to the embryonal origin of neuroblastomas and discuss possible new avenues in the therapeutic approach of future neuroblastoma patients. PMID:14697505

  14. A repetitive elements perspective in Polycomb epigenetics.

    Directory of Open Access Journals (Sweden)

    Valentina eCasa

    2012-10-01

    Full Text Available Repetitive elements comprise over two-thirds of the human genome. For a long time, these elements have received little attention since they were considered non functional. On the contrary, recent evidence indicates that they play central roles in genome integrity, gene expression and disease. Indeed, repeats display meiotic instability associated with disease and are located within common fragile sites, which are hotspots of chromosome rearrangements in tumors. Moreover, a variety of diseases have been associated with aberrant transcription of repetitive elements. Overall this indicates that appropriate regulation of repetitive elements’ activity is fundamental.Polycomb group (PcG proteins are epigenetic regulators that are essential for the normal development of multicellular organisms. Mammalian PcG proteins are involved in fundamental processes, such as cellular memory, cell proliferation, genomic imprinting, X-inactivation, and cancer development. PcG proteins can convey their activity through long-distance interactions also on different chromosomes. This indicates that the 3D organization of PcG proteins contributes significantly to their function. However, it is still unclear how these complex mechanisms are orchestrated and which role PcG proteins play in the multi-level organization of gene regulation. Intriguingly, the greatest proportion of Polycomb-mediated chromatin modifications is located in genomic repeats and it has been suggested that they could provide a binding platform for Polycomb proteins.Here, these lines of evidence are woven together to discuss how repetitive elements could contribute to chromatin organization in the 3D nuclear space.

  15. Individual epigenetic variation: When, why, and so what?

    Science.gov (United States)

    Epigenetics provides a potential explanation for how environmental factors modify the risk for common diseases among individuals. Interindividual variation in DNA methylation and epigenetic regulation has been reported at specific genomic regions including transposable elements, genomically imprinte...

  16. Epigenetic Mechanisms Facilitating Oligodendrocyte Development, Maturation, and Aging

    NARCIS (Netherlands)

    Copray, Sjef; Huynh, Jimmy Long; Sher, Falak; Casaccia-Bonnefil, Patrizia; Boddeke, Erik

    2009-01-01

    The process of oligodendrocyte differentiation is regulated by a dynamic interaction between a genetic and an epigenetic program. Recent studies, addressing nucleosomal histone modifications have considerably increased our knowledge regarding epigenetic regulation of gene expression during oligodend

  17. Epigenetics of Alzheimer’s Disease and Frontotemporal Dementia

    OpenAIRE

    Veerappan, Chendhore S; Sleiman, Sama; Coppola, Giovanni

    2013-01-01

    This article will review the recent advances in the understanding of the role of epigenetic modifications and the promise of future epigenetic therapy in neurodegenerative dementias, including Alzheimer’s disease and frontotemporal dementia.

  18. Interactions between epigenetics and metabolism in cancers

    Directory of Open Access Journals (Sweden)

    JihyeYun

    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.

  19. Epigenetics: A key paradigm in reproductive health

    Science.gov (United States)

    Bunkar, Neha; Pathak, Neelam; Lohiya, Nirmal Kumar

    2016-01-01

    It is well established that there is a heritable element of susceptibility to chronic human ailments, yet there is compelling evidence that some components of such heritability are transmitted through non-genetic factors. Due to the complexity of reproductive processes, identifying the inheritance patterns of these factors is not easy. But little doubt exists that besides the genomic backbone, a range of epigenetic cues affect our genetic programme. The inter-generational transmission of epigenetic marks is believed to operate via four principal means that dramatically differ in their information content: DNA methylation, histone modifications, microRNAs and nucleosome positioning. These epigenetic signatures influence the cellular machinery through positive and negative feedback mechanisms either alone or interactively. Understanding how these mechanisms work to activate or deactivate parts of our genetic programme not only on a day-to-day basis but also over generations is an important area of reproductive health research. PMID:27358824

  20. Epigenetics, cellular memory and gene regulation.

    Science.gov (United States)

    Henikoff, Steven; Greally, John M

    2016-07-25

    The field described as 'epigenetics' has captured the imagination of scientists and the lay public. Advances in our understanding of chromatin and gene regulatory mechanisms have had impact on drug development, fueling excitement in the lay public about the prospects of applying this knowledge to address health issues. However, when describing these scientific advances as 'epigenetic', we encounter the problem that this term means different things to different people, starting within the scientific community and amplified in the popular press. To help researchers understand some of the misconceptions in the field and to communicate the science accurately to each other and the lay audience, here we review the basis for many of the assumptions made about what are currently referred to as epigenetic processes. PMID:27458904

  1. Alcohol-induced histone acetylation reveals a gene network involved in alcohol tolerance.

    Directory of Open Access Journals (Sweden)

    Alfredo Ghezzi

    Full Text Available Sustained or repeated exposure to sedating drugs, such as alcohol, triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state. Alcohol-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most of which may not make any meaningful contribution to the ethanol response under study. Here we used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct alcohols. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. We surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. We identified a network of genes that are essential for the development of tolerance to sedation by alcohol.

  2. Epigenetic cell response to an influence of ionizing radiation

    International Nuclear Information System (INIS)

    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

  3. Physics of epigenetic landscapes and statistical inference by cells

    Science.gov (United States)

    Lang, Alex H.

    Biology is currently in the midst of a revolution. Great technological advances have led to unprecedented quantitative data at the whole genome level. However, new techniques are needed to deal with this deluge of high-dimensional data. Therefore, statistical physics has the potential to help develop systems biology level models that can incorporate complex data. Additionally, physicists have made great strides in understanding non-equilibrium thermodynamics. However, the consequences of these advances have yet to be fully incorporated into biology. There are three specific problems that I address in my dissertation. First, a common metaphor for describing development is a rugged "epigenetic landscape'' where cell fates are represented as attracting valleys resulting from a complex regulatory network. I introduce a framework for explicitly constructing epigenetic landscapes that combines genomic data with techniques from spin-glass physics. The model reproduces known reprogramming protocols and identifies candidate transcription factors for reprogramming to novel cell fates, suggesting epigenetic landscapes are a powerful paradigm for understanding cellular identity. Second, I examine the dynamics of cellular reprogramming. By reanalyzing all available time-series data, I show that gene expression dynamics during reprogramming follow a simple one-dimensional reaction coordinate that is independent of both the time and details of experimental protocol used. I show that such a reaction coordinate emerges naturally from epigenetic landscape models of cell identity where cellular reprogramming is viewed as a "barrier-crossing'' between the starting and ending cell fates. Overall, the analysis and model suggest that gene expression dynamics during reprogramming follow a canonical trajectory consistent with the idea of an ``optimal path'' in gene expression space for reprogramming. Third, an important task of cells is to perform complex computations in response to

  4. [The alchemy--epigenetic regulation of pluripotency].

    Science.gov (United States)

    Bem, Joanna; Grabowska, Iwona

    2013-01-01

    Embryonic stem cells (ESCs) self renew their population, also they are pluripotent which means they can differentiate into any given cell type. In specific culture conditions they remain undifferentiated. On the cellular level pluripotency is determined by many transcription factors, e.g. Sox2, Nanog, Klf4, Oct4. Epigenetic regulation is also crucial for both self renewal and pluripotency. This review focuses on epigenetic mechanisms, among them DNA methylation, posttranslational histone modifications, ATP dependent chromatin remodeling and miRNAs interactions. These mechanisms affect embryonic stem cells functions keeping them poised for differentiation. PMID:24044279

  5. 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.

  6. Epigenetics of dominance for enzyme activity

    Indian Academy of Sciences (India)

    Kuldip S Trehan; Kulbir S Gill

    2002-03-01

    We have isolated and purified two parental homodimers and a unique heterodimer of acid phosphatase [coded by Acph-11.05() and Acph-10.95()] from isogenic homozygotes and heterozygotes of Drosophila malerkotliana. 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 enzyme activity.

  7. 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.

  8. Epigenetically Mediated Pathogenic Effects of Phenanthrene on Regulatory T Cells

    Directory of Open Access Journals (Sweden)

    Jing Liu

    2013-01-01

    Full Text Available Phenanthrene (Phe, a polycyclic aromatic hydrocarbon (PAH, is a major constituent of urban air pollution. There have been conflicting results regarding the role of other AhR ligands 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD and 6-formylindolo [3,2-b]carbazole (FICZ in modifying regulatory T cell populations (Treg or T helper (Th17 differentiation, and the effects of Phe have been understudied. We hypothesized that different chemical entities of PAH induce Treg to become either Th2 or Th17 effector T cells through epigenetic modification of FOXP3. To determine specific effects on T cell populations by phenanthrene, primary human Treg were treated with Phe, TCDD, or FICZ and assessed for function, gene expression, and phenotype. Methylation of CpG sites within the FOXP3 locus reduced FOXP3 expression, leading to impaired Treg function and conversion of Treg into a CD4+CD25lo Th2 phenotype in Phe-treated cells. Conversely, TCDD treatment led to epigenetic modification of IL-17A and conversion of Treg to Th17 T cells. These findings present a mechanism by which exposure to AhR-ligands mediates human T cell responses and begins to elucidate the relationship between environmental exposures, immune modulation, and initiation of human disease.

  9. The chondroitin/dermatan sulfate synthesizing and modifying enzymes in laryngeal cancer: Expressional and epigenetic studies

    OpenAIRE

    Kalathas, Dimitrios; Triantaphyllidou, Irene-Eva; Mastronikolis, Nicholas S; Goumas, Panos D; Papadas, Thoedore A; Tsiropoulos, Gabriel; Vynios, Demitrios H.

    2010-01-01

    Background Significant biochemical changes are observed in glycosaminoglycans in squamous cell laryngeal carcinoma. The most characteristics are in chondroitin/dermatan sulfate fine structure and proportion, which might be due to differential expression of the enzymes involved in their biosynthesis. The aim of the present work was the investigation in expressional and epigenetic level of the enzymes involved in chondroitin/dermatan sulfate biosynthesis in laryngeal cancer. Methods Tissues sub...

  10. Metabotropic Glutamate 2/3 Receptors and Epigenetic Modifications in Psychotic Disorders: A Review

    OpenAIRE

    Matrisciano, Francesco; Panaccione, Isabella; Grayson, Danis R.; Nicoletti, Ferdinando; Guidotti, Alessandro

    2016-01-01

    Schizophrenia and Bipolar Disorder are chronic psychiatric disorders, both considered as “major psychosis”; they are thought to share some pathogenetic factors involving a dysfunctional gene x environment interaction. Alterations in the glutamatergic transmission have been suggested to be involved in the pathogenesis of psychosis. Our group developed an epigenetic model of schizophrenia originated by Prenatal Restraint Stress (PRS) paradigm in mice. PRS mice developed some behavioral alterati...

  11. Global challenges and strategies for control, conversion and utilization of CO{sub 2} for sustainable development involving energy, catalysis, adsorption and chemical processing

    Energy Technology Data Exchange (ETDEWEB)

    Song, Chunshan [Clean Fuels and Catalysis Program, The Energy Institute, and Department of Energy and Geo-Environmental Engineering, The Pennsylvania State University 209 Academic Projects Building, University Park, PA 16802 (United States)

    2006-06-30

    Utilization of carbon dioxide (CO{sub 2}) has become an important global issue due to the significant and continuous rise in atmospheric CO{sub 2} concentrations, accelerated growth in the consumption of carbon-based energy worldwide, depletion of carbon-based energy resources, and low efficiency in current energy systems. The barriers for CO{sub 2} utilization include: (1) costs of CO{sub 2} capture, separation, purification, and transportation to user site; (2) energy requirements of CO{sub 2} chemical conversion (plus source and cost of co-reactants); (3) market size limitations, little investment-incentives and lack of industrial commitments for enhancing CO{sub 2}-based chemicals; and (4) the lack of socio-economical driving forces. The strategic objectives may include: (1) use CO{sub 2} for environmentally-benign physical and chemical processing that adds value to the process; (2) use CO{sub 2} to produce industrially useful chemicals and materials that adds value to the products; (3) use CO{sub 2} as a beneficial fluid for processing or as a medium for energy recovery and emission reduction; and (4) use CO{sub 2} recycling involving renewable sources of energy to conserve carbon resources for sustainable development. The approaches for enhancing CO{sub 2} utilization may include one or more of the following: (1) for applications that do not require pure CO{sub 2}, develop effective processes for using the CO{sub 2}-concentrated flue gas from industrial plants or CO{sub 2}-rich resources without CO{sub 2} separation; (2) for applications that need pure CO{sub 2}, develop more efficient and less-energy intensive processes for separation of CO{sub 2} selectively without the negative impacts of co-existing gases such as H{sub 2}O, O{sub 2}, and N{sub 2}; (3) replace a hazardous or less-effective substance in existing processes with CO{sub 2} as an alternate medium or solvent or co-reactant or a combination of them; (4) make use of CO{sub 2} based on the unique

  12. 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…

  13. Epigenetic alteration of sedimentary rocks at hydrogenic uranium deposit

    International Nuclear Information System (INIS)

    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

  14. Chd1 remodelers maintain open chromatin and regulate the epigenetics of differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Persson, Jenna [Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institutet (Sweden); Ekwall, Karl, E-mail: karl.ekwall@ki.se [Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institutet (Sweden); School of Life Sciences, University College Sodertorn, NOVUM, Huddinge (Sweden)

    2010-05-01

    Eukaryotic DNA is packaged around octamers of histone proteins into nucleosomes, the basic unit of chromatin. In addition to enabling meters of DNA to fit within the confines of a nucleus, the structure of chromatin has functional implications for cell identity. Covalent chemical modifications to the DNA and to histones, histone variants, ATP-dependent chromatin remodelers, small noncoding RNAs and the level of chromatin compaction all contribute to chromosomal structure and to the activity or silencing of genes. These chromatin-level alterations are defined as epigenetic when they are heritable from mother to daughter cell. The great diversity of epigenomes that can arise from a single genome permits a single, totipotent cell to generate the hundreds of distinct cell types found in humans. Two recent studies in mouse and in fly have highlighted the importance of Chd1 chromatin remodelers for maintaining an open, active chromatin state. Based on evidence from fission yeast as a model system, we speculate that Chd1 remodelers are involved in the disassembly of nucleosomes at promoter regions, thus promoting active transcription and open chromatin. It is likely that these nucleosomes are specifically marked for disassembly by the histone variant H2A.Z.

  15. Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives

    Directory of Open Access Journals (Sweden)

    Prakash Chelladurai

    2016-06-01

    Full Text Available Pulmonary arterial hypertension (PAH is a severe and progressive disease, characterised by high pulmonary artery pressure that usually culminates in right heart failure. Recent findings of alterations in the DNA methylation state of superoxide dismutase 2 and granulysin gene loci; histone H1 levels; aberrant expression levels of histone deacetylases and bromodomain-containing protein 4; and dysregulated microRNA networks together suggest the involvement of epigenetics in PAH pathogenesis. Thus, PAH pathogenesis evidently involves the interplay of a predisposed genetic background, epigenetic state and injurious events. Profiling the genome-wide alterations in the epigenetic mechanisms, such as DNA methylation or histone modification pattern in PAH vascular cells, may explain the great variability in susceptibility and disease severity that is frequently associated with pronounced remodelling and worse clinical outcome. Moreover, the influence of genetic predisposition and the acquisition of epigenetic alterations in response to environmental cues in PAH progression and establishment has largely been unexplored on a genome-wide scale. In order to gain insights into the molecular mechanisms leading to the development of PAH and to design novel therapeutic strategies, high-throughput approaches have to be adopted to facilitate systematic identification of the disease-specific networks using next-generation sequencing technologies, the application of these technologies in PAH has been relatively trivial to date.

  16. Epigenetics and Primary Biliary Cirrhosis: a Comprehensive Review and Implications for Autoimmunity.

    Science.gov (United States)

    Xie, Yu-Qing; Ma, Hong-Di; Lian, Zhe-Xiong

    2016-06-01

    Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that develops based upon the interaction of genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified dozens of predisposing variants including HLA, IL12A, and CTLA4 but have been disappointed in identifying a "smoking gun." These discoveries highlight the importance of the genetic background involved in immunological dysregulation. Although concordance rate of PBC in monozygotic (MZ) twins is among the highest reported in autoimmune disorders, incomplete disease concordance in twins associated with differentially expressed genes has been demonstrated. However, little is understood about how environmental aspects contribute to the disease and why middle-aged women are more susceptible. As a result, epigenetic factors, which convert signals indicating environmental changes into dynamic and heritable alterations of transcriptional potential, are getting increased attention by researchers in both basic and clinical studies. Among epigenetic mechanisms, the instability and skewed gene expression in the X chromosome may account for the female preponderance in PBC. In addition, transcriptional regulation of histone modification and DNA methylation underscores potential involvement in disease pathogenesis. High-throughput techniques are being used to identify epigenetic regulators. In this review, we attempt to outline recent progress regarding epigenetics in PBC and other autoimmune diseases. PMID:26267705

  17. 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

    Foetal development of germ cells is a unique biological process orchestrated by cellular specification, migration and niche development in concert with extensive epigenetic and transcriptional programs. Many of these processes take place early in foetal life and are hence very difficult to study....... 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......K9me2, H3K27me3 and H3K9ac. We also show that CIS cells contain high levels of H3K27ac, which is known to mark active enhancers. Proper epigenetic reprogramming seems to be a pre-requisite of normal foetal germ cell development and we propose that alterations in these programs may be a pathogenic...

  18. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Directory of Open Access Journals (Sweden)

    Miller Dianne M

    2008-01-01

    Full Text Available Background Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH, and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. Methods A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Results Eighteen (37% of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5, clear cell (n = 4, or low grade serous (n = 2 carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. Conclusion High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic, BRCA1 loss (epigenetic, and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  19. Radiation-Induced Epigenetic Alterations after Low and High LET Irradiations

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-02-01

    Epigenetics, including DNA methylation and microRNA (miRNA) expression, could be the missing link in understanding the delayed, non-targeted effects of radiation including radiationinduced genomic instability (RIGI). This study tests the hypothesis that irradiation induces epigenetic aberrations, which could eventually lead to RIGI, and that the epigenetic aberrations induced by low linear energy transfer (LET) irradiation are different than those induced by high LET irradiations. GM10115 cells were irradiated with low LET x-rays and high LET iron (Fe) ions and evaluated for DNA damage, cell survival and chromosomal instability. The cells were also evaluated for specific locus methylation of nuclear factor-kappa B (NFκB), tumor suppressor in lung cancer 1 (TSLC1) and cadherin 1 (CDH1) gene promoter regions, long interspersed nuclear element 1 (LINE-1) and Alu repeat element methylation, CpG and non-CpG global methylation and miRNA expression levels. Irradiated cells showed increased micronucleus induction and cell killing immediately following exposure, but were chromosomally stable at delayed times post-irradiation. At this same delayed time, alterations in repeat element and global DNA methylation and miRNA expression were observed. Analyses of DNA methylation predominantly showed hypomethylation, however hypermethylation was also observed. MiRNA shown to be altered in expression level after x-ray irradiation are involved in chromatin remodeling and DNA methylation. Different and higher incidence of epigenetic changes were observed after exposure to low LET x-rays than high LET Fe ions even though Fe ions elicited more chromosomal damage and cell killing. This study also shows that the irradiated cells acquire epigenetic changes even though they are chromosomally stable suggesting that epigenetic aberrations may arise in the cell without initiating RIGI.

  20. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

    2008-05-02

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  1. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray,Joe; Huntsman, David G.

    2007-07-23

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  2. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    International Nuclear Information System (INIS)

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways

  3. Identification of Epigenetic Factor Proteins Expressed in Human Embryonic Stem Cell-Derived Trophoblasts and in Human Placental Trophoblasts.

    Science.gov (United States)

    Sarkar, Prasenjit; Mischler, Adam; Randall, Shan M; Collier, Timothy S; Dorman, Karen F; Boggess, Kim A; Muddiman, David C; Rao, Balaji M

    2016-08-01

    Human embryonic stem cells (hESCs) have been used to derive trophoblasts through differentiation in vitro. Intriguingly, mouse ESCs are prevented from differentiation to trophoblasts by certain epigenetic factor proteins such as Dnmt1, thus necessitating the study of epigenetic factor proteins during hESC differentiation to trophoblasts. We used stable isotope labeling by amino acids in cell culture and quantitative proteomics to study changes in the nuclear proteome during hESC differentiation to trophoblasts and identified changes in the expression of 30 epigenetic factor proteins. Importantly, the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B were downregulated. Additionally, we hypothesized that nuclear proteomics of hESC-derived trophoblasts may be used for screening epigenetic factor proteins expressed by primary trophoblasts in human placental tissue. Accordingly, we conducted immunohistochemistry analysis of six epigenetic factor proteins identified from hESC-derived trophoblasts-DNMT1, DNMT3B, BAF155, BAF60A, BAF57, and ING5-in 6-9 week human placentas. Indeed, expression of these proteins was largely, though not fully, consistent with that observed in 6-9 week placental trophoblasts. Our results support the use of hESC-derived trophoblasts as a model for placental trophoblasts, which will enable further investigation of epigenetic factors involved in human trophoblast development. PMID:27378238

  4. Nuclear-encoded mitochondrial MTO1 and MRPL41 are regulated in an opposite epigenetic mode based on estrogen receptor status in breast cancer

    International Nuclear Information System (INIS)

    MTO1 and MRPL41 are nuclear-encoded mitochondrial genes encoding a mitochondrial tRNA-modifying enzyme and a mitochondrial ribosomal protein, respectively. Although both genes have been known to have potential roles in cancer, little is known about their molecular regulatory mechanism, particularly from an epigenetic approach. In this study, we aimed to address their epigenetic regulation through the estrogen receptor (ER) in breast cancer. Digital differential display (DDD) was conducted to identify mammary gland-specific gene candidates including MTO1 and MRPL41. Promoter CpG methylation and expression in breast cancer cell lines and tissues were examined by methylation-specific PCR and real time RT-PCR. Effect of estradiol (E2), tamoxifen, and trichostatin A (TSA) on gene expression was examined in ER + and ER- breast cancer cell lines. Chromatin immunoprecipitation and luciferase reporter assay were performed to identify binding and influencing of the ER to the promoters. Examination of both cancer tissues and cell lines revealed that the two genes showed an opposite expression pattern according to ER status; higher expression of MTO1 and MRPL41 in ER- and ER+ cancer types, respectively, and their expression levels were inversely correlated with promoter methylation. Tamoxifen, E2, and TSA upregulated MTO1 expression only in ER+ cells with no significant changes in ER- cells. However, these chemicals upregulated MRPL41 expression only in ER- cells without significant changes in ER+ cells, except for tamoxifen that induced downregulation. Chromatin immunoprecipitation and luciferase reporter assay identified binding and influencing of the ER to the promoters and the binding profiles were differentially regulated in ER+ and ER- cells. These results indicate that different epigenetic status including promoter methylation and different responses through the ER are involved in the differential expression of MTO1 and MRPL41 in breast cancer

  5. The epigenetics of estrogen: Epigenetic regulation of hormone-induced memory enhancement

    OpenAIRE

    Frick, Karyn M.; Zhao, Zaorui; Fan, Lu

    2011-01-01

    Epigenetic processes have been implicated in everything from cell proliferation to maternal behavior. Epigenetic alterations, including histone alterations and DNA methylation, have also been shown to play critical roles in the formation of some types of memory, and in the modulatory effects that factors, such as stress, drugs of abuse and environmental stimulation, have on the brain and memory function. Recently, we demonstrated that the ability of the sex-steroid hormone 17β-estradiol (E2) ...

  6. The epigenetic landscape of clear-cell renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Katarzyna Kluzek

    2015-05-01

    Full Text Available Clear cell renal cell carcinoma (ccRCC is the most common subtype of all kidney tumors. During the last few years, epigenetics has emerged as an important mechanism in ccRCC pathogenesis. Recent reports, involving large-scale methylation and sequencing analyses, have identified genes frequently inactivated by promoter methylation and recurrent mutations in genes encoding chromatin regulatory proteins. Interestingly, three of detected genes (PBRM1, SETD2 and BAP1 are located on chromosome 3p, near the VHL gene, inactivated in over 80% ccRCC cases. This suggests that 3p alterations are an essential part of ccRCC pathogenesis. Moreover, most of the proteins encoded by these genes cooperate in histone H3 modifications. The aim of this review is to summarize the latest discoveries shedding light on deregulation of chromatin machinery in ccRCC. Newly described ccRCC-specific epigenetic alterations could potentially serve as novel diagnostic and prognostic biomarkers and become an object of novel therapeutic strategies.

  7. 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

  8. An epigenetic hypothesis for the genomic memory of pain.

    Directory of Open Access Journals (Sweden)

    Sebastian eAlvarado

    2015-03-01

    Full Text Available Chronic pain is accompanied with long-term sensory, affective and cognitive disturbances. What are the mechanisms that mediate the long-term consequences of painful experiences and embed them in the genome? We hypothesize that alterations in DNA methylation, an enzymatic covalent modification of cytosine bases in DNA, serve as a genomic memory of pain in the adult cortex. DNA methylation is an epigenetic mechanism for long-term regulation of gene expression. Neuronal plasticity at the neuroanatomical, functional, morphological, physiological and molecular levels has been demonstrated throughout the neuroaxis in response to persistent pain, including in the adult prefrontal cortex (PFC. We have previously reported widespread changes in gene expression and DNA methylation in the PFC many months following peripheral nerve injury. In support of this hypothesis, we show here that up-regulation of a gene involved with synaptic function, Synaptotagmin II (syt2, in the PFC in a chronic pain model is associated with long-term changes in DNA methylation. The challenges of understanding the contributions of epigenetic mechanisms such as DNA methylation within the PFC to pain chronicity and their therapeutic implications are discussed.

  9. Phenotype as Agent for Epigenetic Inheritance.

    Science.gov (United States)

    Torday, John S; Miller, William B

    2016-01-01

    The conventional understanding of phenotype is as a derivative of descent with modification through Darwinian random mutation and natural selection. Recent research has revealed Lamarckian inheritance as a major transgenerational mechanism for environmental action on genomes whose extent is determined, in significant part, by germ line cells during meiosis and subsequent stages of embryological development. In consequence, the role of phenotype can productively be reconsidered. The possibility that phenotype is directed towards the effective acquisition of epigenetic marks in consistent reciprocation with the environment during the life cycle of an organism is explored. It is proposed that phenotype is an active agent in niche construction for the active acquisition of epigenetic marks as a dominant evolutionary mechanism rather than a consequence of Darwinian selection towards reproductive success. The reproductive phase of the life cycle can then be appraised as a robust framework in which epigenetic inheritance is entrained to affect growth and development in continued reciprocal responsiveness to environmental stresses. Furthermore, as first principles of physiology determine the limits of epigenetic inheritance, a coherent justification can thereby be provided for the obligate return of all multicellular eukaryotes to the unicellular state. PMID:27399791

  10. Epigenetics and Systemic Lupus Erythematosus: Unmet Needs.

    Science.gov (United States)

    Meroni, Pier Luigi; Penatti, Alessandra Emiliana

    2016-06-01

    Systemic lupus erythematosus (SLE) is a chronic relapsing-remitting autoimmune disease affecting several organs. Although the management of lupus patients has improved in the last years, several aspects still remain challenging. More sensitive and specific biomarkers for an early diagnosis as well as for monitoring disease activity and tissue damage are needed. Genome-wide association and gene mapping studies have supported the genetic background for SLE susceptibility. However, the relatively modest risk association and the studies in twins have suggested a role for environmental and epigenetic factors, as well as genetic-epigenetic interaction. Accordingly, there is evidence that differences in DNA methylation, histone modifications, and miRNA profiling can be found in lupus patients versus normal subjects. Moreover, impaired DNA methylation on the inactive X-chromosome was suggested to explain, at least in part, the female prevalence of the disease. Epigenetic markers may be help in fulfilling the unmet needs for SLE by offering new diagnostic tools, new biomarkers for monitoring disease activity, or to better characterize patients with a silent clinical disease but with an active serology. Anti-DNA, anti-phospholipid, and anti-Ro/SSA autoantibodies are thought to be pathogenic for glomerulonephritis, recurrent thrombosis and miscarriages, and neonatal lupus, respectively. However, tissue damage occurs occasionally or, in some patients, only in spite of the persistent presence of the antibodies. Preliminary studies suggest that epigenetic mechanisms may explain why the damage takes place in some patients only or at a given time. PMID:26206675

  11. 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.

  12. Epigenetic Systems View of Human Development.

    Science.gov (United States)

    Gottlieb, Gilbert

    1991-01-01

    Discusses the history of the hierarchical epigenetic systems view as applied to human development and offers examples of its implementation. Notes the agreement by many authors that the multilevel systems view is the right model for developmental psychology in both human and animal studies. (BC)

  13. Design and Synthesis of Epigenetic Drugs

    DEFF Research Database (Denmark)

    Leurs, Ulrike

    2014-01-01

    Epigenetics have within the last decade evolved into an exciting new strategy to target diseases linked to changes in the transcriptome of a cell. Both DNA methylation and posttranslational modifications of histone proteins are important regulators of gene expression, and aberrant regulation...

  14. 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...

  15. 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...

  16. Epigenetic control of embryonic stem cell fate

    DEFF Research Database (Denmark)

    Christophersen, Nicolaj Strøyer; Helin, Kristian

    2010-01-01

    be induced rapidly to differentiate. Maintaining this balance of stability versus plasticity is a challenge, and extensive studies in recent years have focused on understanding the contributions of transcription factors and epigenetic enzymes to the "stemness" properties of these cells. Identifying...

  17. Chromatin and epigenetics in all their states

    NARCIS (Netherlands)

    Bey, Till; Jamge, Suraj; Klemme, Sonja; Komar, Dorota Natalia; Gall, Le Sabine; Mikulski, Pawel; Schmidt, Martin; Zicola, Johan; Berr, Alexandre

    2016-01-01

    In January 2016, the first Epigenetic and Chromatin Regulation of Plant Traits conference was held in Strasbourg, France. An all-star lineup of speakers, a packed audience of 130 participants from over 20 countries, and a friendly scientific atmosphere contributed to make this conference a meetin

  18. 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…

  19. 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.

  20. 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.

  1. Nonlinear epigenetic variance: review and simulations

    NARCIS (Netherlands)

    K.J. Kan; A. Ploeger; M.E.J. Raijmakers; C.V. Dolan; H.L.J. van der Maas

    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 addit

  2. An Architectural Genetic and Epigenetic Perspective

    OpenAIRE

    Stein, Gary S.; Stein, Janet L.; van Wijnen, Andre; Lian, Jane B.; Zaidi, Sayyed K.; Nickerson, Jeffrey; Montecino, Martin; Young, Daniel

    2010-01-01

    The organization and intranuclear localization of nucleic acids and regulatory proteins contribute to both genetic and epigenetic parameters of biological control. Regulatory machinery in the cell nucleus is functionally compartmentalized in microenvironments (focally organized sites where regulatory factors reside) that provide threshold levels of factors required for transcription, replication, repair and cell survival. The common denominator for nuclear organization of regulatory machinery...

  3. Epigenetics: an emerging player in gastric cancer.

    Science.gov (United States)

    Kang, Changwon; Song, Ji-Joon; Lee, Jaeok; Kim, Mi Young

    2014-06-01

    Cancers, like other diseases, arise from gene mutations and/or altered gene expression, which eventually cause dysregulation of numerous proteins and noncoding RNAs. Changes in gene expression, i.e., upregulation of oncogenes and/or downregulation of tumor suppressor genes, can be generated not only by genetic and environmental factors but also by epigenetic factors, which are inheritable but nongenetic modifications of cellular chromosome components. Identification of the factors that contribute to individual cancers is a prerequisite to a full understanding of cancer mechanisms and the development of customized cancer therapies. The search for genetic and environmental factors has a long history in cancer research, but epigenetic factors only recently began to be associated with cancer formation, progression, and metastasis. Epigenetic alterations of chromatin include DNA methylation and histone modifications, which can affect gene-expression profiles. Recent studies have revealed diverse mechanisms by which chromatin modifiers, including writers, erasers and readers of the aforementioned modifications, contribute to the formation and progression of cancer. Furthermore, functional RNAs, such as microRNAs and long noncoding RNAs, have also been identified as key players in these processes. This review highlights recent findings concerning the epigenetic alterations associated with cancers, especially gastric cancer. PMID:24914365

  4. Epigenetic Modulation in the treatment Atherosclerotic disease

    Directory of Open Access Journals (Sweden)

    Mikaela M Byrne

    2014-10-01

    Full Text Available Cardiovascular disease is the single largest cause of death in the western world and its incidence is on the rise globally. Atherosclerosis, characterised by the development of atheromatus plaque, can trigger luminal narrowing and upon rupture result in myocardial infarction or ischemic stroke. Epigenetic mechanisms are a source of considerable research interest due to the role they play in gene regulation. Epigenetic mechanisms such as DNA methylation and histone acetylation have been identified as potential drug targets in the treatment of cardiovascular disease. miRNAs are known to play a role in gene silencing, which has been widely investigated in cancer. In comparison, the role they play in cardiovascular disease and plaque rupture is not well understood. Nutritional epigenetic modifiers from dietary components, for instance sulforaphane found in broccoli, have been shown to suppress the pro-inflammatory response through transcription factor activation. This review will discuss current and potential epigenetic therapeutics for the treatment of cardiovascular disease, focusing on the use of miRNAs and dietary supplements such as sulforaphane and protocatechuic aldehyde.

  5. Epigenetic architecture and miRNA: reciprocal regulators

    DEFF Research Database (Denmark)

    Wiklund, Erik Digman; Kjems, Jørgen; Clark, Susan

    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....

  6. Epigenetics and etiology of neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Beata M. Gruber

    2011-08-01

    Full Text Available Determination of specific gene profile expression is essential for morphological and functional differentiation of cells in the human organism. The human genome consists of 25–30 thousands genes but only some of them are expressed in each cell. Epigenetic modifications such as DNA methylation, histone and chromatin modifications or non-coding RNA functions are also responsible for the unique gene expression patterns. It is suggested that transcriptional gene activation is related to hypomethylation and the transcriptionally non-active sequences are hypermethylated. Covalent histone modifications and DNA methylation are correlated and interacting. Chromatin modeling is regulated not only by specific enzymes but also by protein kinases or phosphatases and coactivators, such as CBP. Such interaction makes the “histone code” which with the chromatin proteins determines gene expression patterns as the response to external agents. Evidence of a major role for epigenetic modifications in neurological disease has come from three converging lines of enquiry: high conservation throughout evolution of the histone residues that are the target for epigenetic modifications; association between mutations in epigenetic components and multisystem disease syndrome in the nervous system; and broad efficacy of small-molecule epigenetic modulators, e.g. histone deacetylase inhibitors, in models of neurological diseases incurable up to now, such as Huntington’s disease, (HD, Parkinson’s disease (PD and Alzheimer’s disease (AD. This article is a survey of the literature concerning the characterization of gene expression patterns correlated with some neurodegenerative diseases. The processes of DNA hypomethylation and histone acetylation are emphasized. The histone deacetylases are indicated as the basis for design of potential drugs.

  7. Natural epigenetic variation in bats and its role in evolution.

    Science.gov (United States)

    Liu, Sen; Sun, Keping; Jiang, Tinglei; Feng, Jiang

    2015-01-01

    When facing the challenges of environmental change, such as habitat fragmentation, organisms have to adjust their phenotype to adapt to various environmental stresses. Recent studies show that epigenetic modifications could mediate environmentally induced phenotypic variation, and this epigenetic variance could be inherited by future generations, indicating that epigenetic processes have potential evolutionary effects. Bats living in diverse environments show geographic variations in phenotype, and the females usually have natal philopatry, presenting an opportunity to explore how environments shape epigenetic marks on the genome and the evolutionary potential of epigenetic variance in bat populations for adaptation. We have explored the natural epigenetic diversity and structure of female populations of the great roundleaf bat (Hipposideros armiger), the least horseshoe bat (Rhinolophus pusillus) and the eastern bent-winged bat (Miniopterus fuliginosus) using a methylation-sensitive amplified polymorphism technique. We have also estimated the effects of genetic variance and ecological variables on epigenetic diversification. All three bat species have a low level of genomic DNA methylation and extensive epigenetic diversity that exceeds the corresponding genetic variance. DNA sequence divergence, epigenetic drift and environmental variables contribute to the epigenetic diversities of each species. Environment-induced epigenetic variation may be inherited as a result of both mitosis and meiosis, and their potential roles in evolution for bat populations are also discussed in this review. PMID:25568456

  8. Epigenetics and Transcriptomics to Detect Adverse Drug Effects in Model Systems of Human Development

    OpenAIRE

    Balmer, Nina V.; Leist, Marcel

    2014-01-01

    Prenatal exposure to environmental chemicals or drugs has been associated with functional or structural deficits and the development of diseases in later life. For example, developmental neurotoxicity (DNT) is triggered by lead, and this compound may predispose to neurodegenerative diseases in later life. The molecular memory for such late consequences of early exposure is not known, but epigenetic mechanisms (modification of the chromatin structure) could take this role. Examples and underly...

  9. Epigenetic Mechanisms in Bone Biology and Osteoporosis: Can They Drive Therapeutic Choices?

    Science.gov (United States)

    Marini, Francesca; Cianferotti, Luisella; Brandi, Maria Luisa

    2016-01-01

    Osteoporosis is a complex multifactorial disorder of the skeleton. Genetic factors are important in determining peak bone mass and structure, as well as the predisposition to bone deterioration and fragility fractures. Nonetheless, genetic factors alone are not sufficient to explain osteoporosis development and fragility fracture occurrence. Indeed, epigenetic factors, representing a link between individual genetic aspects and environmental influences, are also strongly suspected to be involved in bone biology and osteoporosis. Recently, alterations in epigenetic mechanisms and their activity have been associated with aging. Also, bone metabolism has been demonstrated to be under the control of epigenetic mechanisms. Runt-related transcription factor 2 (RUNX2), the master transcription factor of osteoblast differentiation, has been shown to be regulated by histone deacetylases and microRNAs (miRNAs). Some miRNAs were also proven to have key roles in the regulation of Wnt signalling in osteoblastogenesis, and to be important for the positive or negative regulation of both osteoblast and osteoclast differentiation. Exogenous and environmental stimuli, influencing the functionality of epigenetic mechanisms involved in the regulation of bone metabolism, may contribute to the development of osteoporosis and other bone disorders, in synergy with genetic determinants. The progressive understanding of roles of epigenetic mechanisms in normal bone metabolism and in multifactorial bone disorders will be very helpful for a better comprehension of disease pathogenesis and translation of this information into clinical practice. A deep understanding of these mechanisms could help in the future tailoring of proper individual treatments, according to precision medicine’s principles. PMID:27529237

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

    Directory of Open Access Journals (Sweden)

    RobertKumsta

    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.

  11. Theoretical analysis of epigenetic cell memory by nucleosome modification.

    Science.gov (United States)

    Dodd, Ian B; Micheelsen, Mille A; Sneppen, Kim; Thon, Geneviève

    2007-05-18

    Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Such epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of the states are thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. We developed a simplified stochastic model for dynamic nucleosome modification based on the silent mating-type region of the yeast Schizosaccharomyces pombe. We show that the mechanism can give strong bistability that is resistant both to high noise due to random gain or loss of nucleosome modifications and to random partitioning upon DNA replication. However, robust bistability required: (1) cooperativity, the activity of more than one modified nucleosome, in the modification reactions and (2) that nucleosomes occasionally stimulate modification beyond their neighbor nucleosomes, arguing against a simple continuous spreading of nucleosome modification. PMID:17512413

  12. MGMT expression: insights into its regulation. 1. Epigenetic factors

    Directory of Open Access Journals (Sweden)

    Iatsyshyna A. P.

    2013-03-01

    Full Text Available O6-methylguanine-DNA methyltransferase (MGMT is the DNA repair enzyme responsible for removing of alkylation adducts from the O6-guanine in DNA. Despite MGMT prevents mutations and cell death, this enzyme can provide resistance of cancer cells to alkylating agents of chemotherapy. The high intra- and inter-individual variations in the human MGMT expression level have been observed indicating to a complicated regulation of this gene. This review is focused on the study of epigenetic factors which could be potentially involved in regulation of the human MGMT gene expression. These include chromatin remodeling via histone modifications and DNA methylation of promoter region and gene body, as well as RNA-based mechanisms, alternative splicing, protein post- translational modifications, and other.

  13. Great expectations - Epigenetics and the meandering path from bench to bedside.

    Science.gov (United States)

    Häfner, Sophia J; Lund, Anders H

    2016-06-01

    Making quick promises of major biomedical breakthroughs based on exciting discoveries at the bench is tempting. But the meandering path from fundamental science to life-saving clinical applications can be fraught with many hurdles. Epigenetics, the study of potentially heritable changes of gene function without modification of the underlying DNA sequence, has dominated the biological research field during the last decade and encountered a large public success. Driven by the unfolding of molecular biology and recent technological progress, the term has evolved significantly and shifted from a conceptual framework to a mechanistic understanding. This shift was accompanied by much hype and raised high hopes that epigenetics might hold both the key to deciphering the molecular underpinning of complex, non-Mendelian diseases and offer novel therapeutic approaches for a large panel of pathologies. However, while exciting reports of biological phenomena involving DNA methylation and histone modifications fill up the scientific literature, the realistic clinical applications of epigenetic medicines remain somewhat blurry. Here, we discuss the state of the art and speculate how epigenetics might contribute to prognostic and therapy approaches in the future. PMID:27621117

  14. Genetics and epigenetics of cutaneous malignant melanoma: a concert out of tune.

    Science.gov (United States)

    van den Hurk, Karin; Niessen, Hanneke E C; Veeck, Jürgen; van den Oord, Joost J; van Steensel, Maurice A M; Zur Hausen, Axel; van Engeland, Manon; Winnepenninckx, Véronique J L

    2012-08-01

    Cutaneous malignant melanoma (CMM) is the most life-threatening neoplasm of the skin and is considered a major health problem as both incidence and mortality rates continue to rise. Once CMM has metastasized it becomes therapy-resistant and is an inevitably deadly disease. Understanding the molecular mechanisms that are involved in the initiation and progression of CMM is crucial for overcoming the commonly observed drug resistance as well as developing novel targeted treatment strategies. This molecular knowledge may further lead to the identification of clinically relevant biomarkers for early CMM detection, risk stratification, or prediction of response to therapy, altogether improving the clinical management of this disease. In this review we summarize the currently identified genetic and epigenetic alterations in CMM development. Although the genetic components underlying CMM are clearly emerging, a complete picture of the epigenetic alterations on DNA (DNA methylation), RNA (non-coding RNAs), and protein level (histone modifications, Polycomb group proteins, and chromatin remodeling) and the combinatorial interactions between these events is lacking. More detailed knowledge, however, is accumulating for genetic and epigenetic interactions in the aberrant regulation of the INK4b-ARF-INK4a and microphthalmia-associated transcription factor (MITF) loci. Importantly, we point out that it is this interplay of genetics and epigenetics that effectively leads to distorted gene expression patterns in CMM. PMID:22503822

  15. Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers.

    Science.gov (United States)

    Seisenberger, Stefanie; Peat, Julian R; Hore, Timothy A; Santos, Fátima; Dean, Wendy; Reik, Wolf

    2013-01-01

    In mammalian development, epigenetic modifications, including DNA methylation patterns, play a crucial role in defining cell fate but also represent epigenetic barriers that restrict developmental potential. At two points in the life cycle, DNA methylation marks are reprogrammed on a global scale, concomitant with restoration of developmental potency. DNA methylation patterns are subsequently re-established with the commitment towards a distinct cell fate. This reprogramming of DNA methylation takes place firstly on fertilization in the zygote, and secondly in primordial germ cells (PGCs), which are the direct progenitors of sperm or oocyte. In each reprogramming window, a unique set of mechanisms regulates DNA methylation erasure and re-establishment. Recent advances have uncovered roles for the TET3 hydroxylase and passive demethylation, together with base excision repair (BER) and the elongator complex, in methylation erasure from the zygote. Deamination by AID, BER and passive demethylation have been implicated in reprogramming in PGCs, but the process in its entirety is still poorly understood. In this review, we discuss the dynamics of DNA methylation reprogramming in PGCs and the zygote, the mechanisms involved and the biological significance of these events. Advances in our understanding of such natural epigenetic reprogramming are beginning to aid enhancement of experimental reprogramming in which the role of potential mechanisms can be investigated in vitro. Conversely, insights into in vitro reprogramming techniques may aid our understanding of epigenetic reprogramming in the germline and supply important clues in reprogramming for therapies in regenerative medicine. PMID:23166394

  16. Gene X Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms

    Directory of Open Access Journals (Sweden)

    SylvieTordjman

    2014-08-01

    Full Text Available Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD. First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene X environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention and early therapeutic intervention of ASD.

  17. Emerging Trends in Epigenetic Regulation of Nutrient Deficiency Response in Plants.

    Science.gov (United States)

    Sirohi, Gunjan; Pandey, Bipin K; Deveshwar, Priyanka; Giri, Jitender

    2016-03-01

    Diverse environmental stimuli largely affect the ionic balance of soil, which have a direct effect on growth and crop yield. Details are fast emerging on the genetic/molecular regulators, at whole-genome levels, of plant responses to mineral deficiencies in model and crop plants. These genetic regulators determine the root architecture and physiological adaptations for better uptake and utilization of minerals from soil. Recent evidence also shows the potential roles of epigenetic mechanisms in gene regulation, driven by minerals imbalance. Mineral deficiency or sufficiency leads to developmental plasticity in plants for adaptation, which is preceded by a change in the pattern of gene expression. Notably, such changes at molecular levels are also influenced by altered chromatin structure and methylation patterns, or involvement of other epigenetic components. Interestingly, many of the changes induced by mineral deficiency are also inheritable in the form of epigenetic memory. Unravelling these mechanisms in response to mineral deficiency would further advance our understanding of this complex plant response. Further studies on such approaches may serve as an exciting interaction model of epigenetic and genetic regulations of mineral homeostasis in plants and designing strategies for crop improvement. PMID:26829932

  18. Transgenerational epigenetic inheritance in mammals: how good is the evidence?

    Science.gov (United States)

    van Otterdijk, Sanne D; Michels, Karin B

    2016-07-01

    Epigenetics plays an important role in orchestrating key biologic processes. Epigenetic marks, including DNA methylation, histones, chromatin structure, and noncoding RNAs, are modified throughout life in response to environmental and behavioral influences. With each new generation, DNA methylation patterns are erased in gametes and reset after fertilization, probably to prevent these epigenetic marks from being transferred from parents to their offspring. However, some recent animal studies suggest an apparent resistance to complete erasure of epigenetic marks during early development, enabling transgenerational epigenetic inheritance. Whether there are similar mechanisms in humans remains unclear, with the exception of epigenetic imprinting. Nevertheless, a distinctly different mechanism-namely, intrauterine exposure to environmental stressors that may affect establishment of the newly composing epigenetic patterns after fertilization-is often confused with transgenerational epigenetic inheritance. In this review, we delineate the definition of and requirement for transgenerational epigenetic inheritance, differentiate it from the consequences of intrauterine exposure, and discuss the available evidence in both animal models and humans.-Van Otterdijk, S. D., Michels, K. B. Transgenerational epigenetic inheritance in mammals: how good is the evidence? PMID:27037350

  19. Epigenetic silencing of glutaminase 2 in human liver and colon cancers

    International Nuclear Information System (INIS)

    Glutaminase 2 (Gls2) is a p53 target gene and is known to play an important role in energy metabolism. Gls2 has been reported to be downregulated in human hepatocellular carcinomas (HCC). However, the underlying mechanism responsible for its downregulation is still unclear. Here, we investigated Gls2 expression and its promoter methylation status in human liver and colon cancers. mRNA expression of Gls2 was determined in human liver and colon cancer cell lines and HCC tissues by real-time PCR and promoter methylation was analyzed by methylation-specific PCR (MSP) and validated by bisulfite genome sequencing (BGS). Cell growth was determined by colony formation assay and MTS assay. Statistical analysis was performed by Wilcoxon matched-pairs test or non-parametric t test. First, we observed reduced Gls2 mRNA level in a selected group of liver and colon cancer cell lines and in the cancerous tissues from 20 HCC and 5 human colon cancer patients in comparison to their non-cancerous counter parts. Importantly, the lower level of Gls2 in cancer cells was closely correlated to its promoter hypermethylation; and chemical demethylation treatment with 5-aza-2′-deoxycytidine (Aza) increased Gls2 mRNA level in both liver and colon cancer cells, indicating that direct epigenetic silencing suppressed Gls2 expression by methylation. Next, we further examined this correlation in human HCC tissues, and 60% of primary liver tumor tissues had higher DNA methylation levels when compared with adjacent non-tumor tissues. Detailed methylation analysis of 23 CpG sites at a 300-bp promoter region by bisulfite genomic sequencing confirmed its methylation. Finally, we examined the biological function of Gls2 and found that restoring Gls2 expression in cancer cells significantly inhibited cancer cell growth and colony formation ability through induction of cell cycle arrest. We provide evidence showing that epigenetic silencing of Gls2 via promoter hypermethylation is common in human liver

  20. Epigenetic modifications and human pathologies: cancer and CVD.

    Science.gov (United States)

    Duthie, Susan J

    2011-02-01

    Epigenetic changes are inherited alterations in DNA that affect gene expression and function without altering the DNA sequence. DNA methylation is one epigenetic process implicated in human disease that is influenced by diet. DNA methylation involves addition of a 1-C moiety to cytosine groups in DNA. Methylated genes are not transcribed or are transcribed at a reduced rate. Global under-methylation (hypomethylation) and site-specific over-methylation (hypermethylation) are common features of human tumours. DNA hypomethylation, leading to increased expression of specific proto-oncogenes (e.g. genes involved in proliferation or metastasis) can increase the risk of cancer as can hypermethylation and reduced expression of tumour suppressor (TS) genes (e.g. DNA repair genes). DNA methyltransferases (DNMT), together with the methyl donor S-adenosylmethionine (SAM), facilitate DNA methylation. Abnormal DNA methylation is implicated not only in the development of human cancer but also in CVD. Polyphenols, a group of phytochemicals consumed in significant amounts in the human diet, effect risk of cancer. Flavonoids from tea, soft fruits and soya are potent inhibitors of DNMT in vitro, capable of reversing hypermethylation and reactivating TS genes. Folates, a group of water-soluble B vitamins found in high concentration in green leafy vegetables, regulate DNA methylation through their ability to generate SAM. People who habitually consume the lowest level of folate or with the lowest blood folate concentrations have a significantly increased risk of developing several cancers and CVD. This review describes how flavonoids and folates in the human diet alter DNA methylation and may modify the risk of human colon cancer and CVD. PMID:21067630

  1. [Transcriptome analysis and epigenetic analysis during osteoclastogenesis].

    Science.gov (United States)

    Nakamura, Shinya; Tanaka, Sakae

    2016-04-01

    The importance of receptor activator of nuclear factor-κB ligand(RANKL)during osteoclastogenesis was discovered in 1998. After that Nfatc1, downstream gene of RANKL-RANK signaling, was identified as a master regulator of osteoclastogenesis by transcriptome analysis. In recent years, with the advancement of epigenetic analysis method and big data analysis technology, epigenetic analysis about osteoclastogenesis gradually progresses. Some papers using H3K4me3 and H3K27me3 histone modification change data, DNase-seq data and formaldehyde-assisted isolation of regulatory elements(FAIRE)-seq data during osteoclastogenesis were published recently. It will probably contribute to elucidate the crosstalk between osteoclasts and osteoblasts, osteocytes or chondrocytes in the future. PMID:27013627

  2. Epigenetic Modifications of Major Depressive Disorder

    Directory of Open Access Journals (Sweden)

    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.

  3. Epigenetic alterations associated with cholangiocarcinoma (review).

    Science.gov (United States)

    Isomoto, Hajime

    2009-08-01

    Cholangiocarcinoma (CCA) is a highly lethal malignant tumor arising from the biliary tract epithelium. Chronic inflammatory conditions, including primary sclerosing cholangitis, liver fluke infestation, and hepatolithiasis, are considered risk factors, but the cause is still unknown in most cases. Recent advances in molecular pathogenesis have highlighted the importance of epigenetic alterations, including promoter hypermethylation and histone deacetylation, in the process of cholangiocarcinogenesis. More recently, research interest has been focusing on microRNA (mir), a major subtype of non-coding RNA. Mir is highly conserved among species and regulates the expression of specific target genes by binding to the 3'-untranslated regions of messenger RNA. The number of studies on a possible link between mir and various cancers is growing. This review provides a comprehensive overview of the genes currently known to be hypermethylated in CCA and their putative roles in cholangiocarcinogenesis. The epigenetic role of mir in the pathogenesis of CCA is also discussed. PMID:19578760

  4. Atherogenic Factors and Their Epigenetic Relationships

    Directory of Open Access Journals (Sweden)

    Ana Z. Fernandez

    2010-01-01

    Full Text Available Hypercholesterolemia, homocysteine, oxidative stress, and hyperglycemia have been recognized as the major risk factors for atherogenesis. Their impact on the physiology and biochemistry of vascular cells has been widely demonstrated for the last century. However, the recent discovery of the role of epigenetics in human disease has opened up a new field in the study of atherogenic factors. Thus, epigenetic tags in endothelial, smooth muscle, and immune cells seem to be differentially affected by similar atherogenic stimuli. This paper summarizes some recent works on expression of histone-modifying enzymes and DNA methylation directly linked to the presence of risk factors that could lead to the development or prevention of the atherosclerotic process.

  5. Epigenetics and the Adaptive Immune Response

    OpenAIRE

    Kondilis-Mangum, Hrisavgi D.; Wade, Paul A.

    2012-01-01

    Cells of the adaptive immune response undergo dynamic epigenetic changes as they develop and respond to immune challenge. Plasticity is a necessary prerequisite for the chromosomal dynamics of lineage specification, development, and the immune effector function of the mature cell types. The alterations in DNA methylation and histone modification that characterize activation may be integral to the generation of immunologic memory, thereby providing an advantage on secondary exposure to pathoge...

  6. Epigenetic Mechanisms of Rubinstein-Taybi Syndrome

    OpenAIRE

    Park, Elizabeth; Kim, Yunha; Ryu, Hyun; Kowall, Neil W.; Lee, Junghee; Ryu, Hoon

    2014-01-01

    Rubinstein-Taybi Syndrome (RTS) is an incurable genetic disorder with combination of mental retardation and physical features including broad thumbs and toes, craniofacial abnormalities, and growth deficiency. While the autosomal dominant mode of transmission is limitedly known, the majority of cases are attributable to de novo mutations in RTS. The first identified gene associated with RTS is CREB-binding protein (CREBBP/CBP). Alterations of the epigenetic ‘histone code’ due to dysfunction o...

  7. Epigenetics and etiology of neurodegenerative diseases

    OpenAIRE

    Beata M. Gruber

    2011-01-01

    Determination of specific gene profile expression is essential for morphological and functional differentiation of cells in the human organism. The human genome consists of 25–30 thousands genes but only some of them are expressed in each cell. Epigenetic modifications such as DNA methylation, histone and chromatin modifications or non-coding RNA functions are also responsible for the unique gene expression patterns. It is suggested that transcriptional gene activation is related to hypomethy...

  8. On the road to epigenetic therapy.

    Science.gov (United States)

    Walton, Emma L

    2016-06-01

    In this issue of the Biomedical Journal, we examine how far the explosion of epigenetic studies in recent years has translated to benefits for patients in the clinic, and we highlight an original study suggesting that increased vegetable intake protects against osteoporotic fractures. We also hear several opinions on the use, or perhaps misuse, of Impact Factor and what the future should hold for this publication metric. PMID:27621116

  9. Epigenetic Influences on Brain Development and Plasticity

    OpenAIRE

    Fagiolini, Michela; Jensen, Catherine L.; Champagne, Frances A.

    2009-01-01

    A fine interplay exists between sensory experience and innate genetic programs leading to the sculpting of neuronal circuits during early brain development. Recent evidence suggests that the dynamic regulation of gene expression through epigenetic mechanisms is at the interface between environmental stimuli and long-lasting molecular, cellular and complex behavioral phenotypes acquired during periods of developmental plasticity. Understanding these mechanisms may give insight into the formati...

  10. Epigenetic Regulation of EBV Persistence and Oncogenesis

    OpenAIRE

    Tempera, Italo; Lieberman, Paul M

    2014-01-01

    Epigenetic mechanisms play a fundamental role in generating diverse and heritable patterns of viral and cellular gene expression. Epstein-Barr Virus (EBV) can adopt a variety of gene expression programs that are necessary for long-term viral persistence and latency in multiple host-cell types and conditions. The latent viral genomes assemble into chromatin structures with different histone and DNA modifications patterns that control viral gene expression. Variations in nucleosome organization...

  11. Noncoding Elements: Evolution and Epigenetic Regulation

    KAUST Repository

    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

  12. Epigenetic targeting of ovarian cancer stem cells.

    Science.gov (United States)

    Wang, Yinu; Cardenas, Horacio; Fang, Fang; Condello, Salvatore; Taverna, Pietro; Segar, Matthew; Liu, Yunlong; Nephew, Kenneth P; Matei, Daniela

    2014-09-01

    Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor-suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cells (OCSC). In this study, we tested the hypothesis that DNA-hypomethylating agents may be able to reset OCSC toward a differentiated phenotype by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH(+) ovarian cancer cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low-dose SGI-110 reduced the stem-like properties of ALDH(+) cells, including their tumor-initiating capacity, resensitized these OCSCs to platinum, and induced reexpression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by reprogramming residual cancer stem-like cells. Furthermore, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer. PMID:25035395

  13. Exploiting tumor epigenetics to improve oncolytic virotherapy

    Directory of Open Access Journals (Sweden)

    Nicole E. Forbes

    2013-09-01

    Full Text Available Oncolytic viruses (OVs comprise a versatile and multi-mechanistic therapeutic platform in the growing arsenal of anticancer biologics. These replicating therapeutics find favorable conditions in the tumor niche, characterized among others by increased metabolism, reduced anti-tumor/antiviral immunity, and disorganized vasculature. Through a self-amplification that is dependent on multiple cancer-specific defects, these agents exhibit remarkable tumor selectivity. With several OVs completing or entering Phase III clinical evaluation, their therapeutic potential as well as the challenges ahead are increasingly clear. One key hurdle is tumor heterogeneity, which results in variations in the ability of tumors to support productive infection by OVs and to induce adaptive anti-tumor immunity. To this end, mounting evidence suggests tumor epigenetics may play a key role. This review will focus on the epigenetic landscape of tumors and how it relates to OV infection. Therapeutic strategies aiming to exploit the epigenetic identity of tumors in order to improve OV therapy are also discussed.

  14. Titration and hysteresis in epigenetic chromatin silencing

    International Nuclear Information System (INIS)

    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. Epigenetics and cardiovascular risk in childhood.

    Science.gov (United States)

    Martino, Francesco; Magenta, Alessandra; Pannarale, Giuseppe; Martino, Eliana; Zanoni, Cristina; Perla, Francesco M; Puddu, Paolo E; Barillà, Francesco

    2016-08-01

    Cardiovascular disease (CVD) can arise at the early stages of development and growth. Genetic and environmental factors may interact resulting in epigenetic modifications with abnormal phenotypic expression of genetic information without any change in the nucleotide sequence of DNA. Maternal dietary imbalance, inadequate to meet the nutritional needs of the fetus can lead to intrauterine growth retardation, decreased gestational age, low birth weight, excessive post-natal growth and metabolic alterations, with subsequent appearance of CVD risk factors. Fetal exposure to high cholesterol, diabetes and maternal obesity is associated with increased risk and progression of atherosclerosis. Maternal smoking during pregnancy and exposure to various environmental pollutants induce epigenetic alterations of gene expression relevant to the onset or progression of CVD. In children with hypercholesterolemia and/or obesity, oxidative stress activates platelets and monocytes, which release proinflammatory and proatherogenic substances, inducing endothelial dysfunction, decreased Doppler flow-mediated dilation and increased carotid intima-media thickness. Primary prevention of atherosclerosis should be implemented early. It is necessary to identify, through screening, high-risk apparently healthy children and take care of them enforcing healthy lifestyle (mainly consisting of Mediterranean diet and physical activity), prescribing nutraceuticals and eventual medications, if required by a high-risk profile. The key issue is the restoration of endothelial function in the reversible stage of atherosclerosis. Epigenetics may provide new markers for an early identification of children at risk and thereby develop innovative therapies and specific nutritional interventions in critical times. PMID:27367935

  16. Epigenetic Changes in Diabetes and Cardiovascular Risk.

    Science.gov (United States)

    Keating, Samuel T; Plutzky, Jorge; El-Osta, Assam

    2016-05-27

    Cardiovascular complications remain the leading causes of morbidity and premature mortality in patients with diabetes mellitus. Studies in humans and preclinical models demonstrate lasting gene expression changes in the vasculopathies initiated by previous exposure to high glucose concentrations and the associated overproduction of reactive oxygen species. The molecular signatures of chromatin architectures that sensitize the genome to these and other cardiometabolic risk factors of the diabetic milieu are increasingly implicated in the biological memory underlying cardiovascular complications and now widely considered as promising therapeutic targets. Atherosclerosis is a complex heterocellular disease where the contributing cell types possess distinct epigenomes shaping diverse gene expression. Although the extent that pathological chromatin changes can be manipulated in human cardiovascular disease remains to be established, the clinical applicability of epigenetic interventions will be greatly advanced by a deeper understanding of the cell type-specific roles played by writers, erasers, and readers of chromatin modifications in the diabetic vasculature. This review details a current perspective of epigenetic mechanisms of macrovascular disease in diabetes mellitus and highlights recent key descriptions of chromatinized changes associated with persistent gene expression in endothelial, smooth muscle, and circulating immune cells relevant to atherosclerosis. Furthermore, we discuss the challenges associated with pharmacological targeting of epigenetic networks to correct abnormal or deregulated gene expression as a strategy to alleviate the clinical burden of diabetic cardiovascular disease. PMID:27230637

  17. [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. PMID:26418595

  18. Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives

    OpenAIRE

    Prakash Chelladurai; Werner Seeger; Soni Savai Pullamsetti

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a severe and progressive disease, characterised by high pulmonary artery pressure that usually culminates in right heart failure. Recent findings of alterations in the DNA methylation state of superoxide dismutase 2 and granulysin gene loci; histone H1 levels; aberrant expression levels of histone deacetylases and bromodomain-containing protein 4; and dysregulated microRNA networks together suggest the involvement of epigenetics in PAH pathogenesis. Th...

  19. Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience

    OpenAIRE

    Kumsta, Robert; Hummel, Elisabeth; Frances S. Chen; Heinrichs, Markus

    2013-01-01

    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...

  20. Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise

    OpenAIRE

    Marta eCosín-Tomás; Alvarez-López, María J; Sandra eSanchez-Roige; Jaume F Lalanza; Sergi eBayod; Coral eSanfeliu; Merce ePallas; Rosa María Escorihuela; Perla eKaliman

    2014-01-01

    The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of vo...

  1. The Patched gene is epigenetically regulated in ovarian dermoids and fibromas, but not in basocellular carcinomas

    OpenAIRE

    Čretnik, Maja; Musani, Vesna; Orešković, Slavko; Leović, Dinko; Levanat, Sonja

    2007-01-01

    The Hedgehog/Patched signaling pathway plays a prominent role during mammalian development but it is also involved in oncogenic transformation. We investigated the methylation status of the Patched promoter in a set of basocellular carcinomas of the skin and ovarian tumors as an alternative to mutational causes of the pathway deregulation. Our aim was to define a possible role of genetic and/or epigenetic mechanisms of Hedgehog/Patched signal transduction in the development of these tumors. B...

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

    OpenAIRE

    RobertKumsta; MarkusHeinrichs

    2013-01-01

    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...

  3. Drug-loaded biodegradable microspheres for image-guided combinatory epigenetic therapy in cells

    OpenAIRE

    Xu, Ronald X.; Xu, Jeff S.; Zuo, Tao; Shen, Rulong; Huang, Tim H.; Michael F. Tweedle

    2011-01-01

    We synthesize drug-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres for image-guided combinatory epigenetic therapy in MCF-10A human mammary epithelial cells. LY294002 and Nile Red are encapsulated in microspheres for sustained drug release and fluorescence microscopic imaging. Drug-loaded microspheres target MCF-10A cells through a three-step binding process involving biotinylated antibody, streptavidin, and biotinylated microspheres. LY294002 loaded microspheres and 5-Aza-2-deoxycy...

  4. Epigenetic Reprogramming of Muscle Progenitors: Inspiration for Clinical Therapies

    Directory of Open Access Journals (Sweden)

    Silvia Consalvi

    2016-01-01

    Full Text Available In the context of regenerative medicine, based on the potential of stem cells to restore diseased tissues, epigenetics is becoming a pivotal area of interest. Therapeutic interventions that promote tissue and organ regeneration have as primary objective the selective control of gene expression in adult stem cells. This requires a deep understanding of the epigenetic mechanisms controlling transcriptional programs in tissue progenitors. This review attempts to elucidate the principle epigenetic regulations responsible of stem cells differentiation. In particular we focus on the current understanding of the epigenetic networks that regulate differentiation of muscle progenitors by the concerted action of chromatin-modifying enzymes and noncoding RNAs. The novel exciting role of exosome-bound microRNA in mediating epigenetic information transfer is also discussed. Finally we show an overview of the epigenetic strategies and therapies that aim to potentiate muscle regeneration and counteract the progression of Duchenne Muscular Dystrophy (DMD.

  5. Epigenetics and complex disease: from etiology to new therapeutics.

    Science.gov (United States)

    Ptak, Carolyn; Petronis, Arturas

    2008-01-01

    Epigenetics is a new development in complex non-Mendelian disease, which may not only uncover etiologic and pathogenic mechanisms but may also provide the basis for the development of medications that would target the primary epigenetic causes of such diseases. Such epigenetic drugs would be novel, potentially possessing substantially higher therapeutic potential and a much lower rate of adverse effects in comparison to current symptomatic treatments. A collection of epigenetic drugs already exist at various stages of development and, although their effectiveness has yet to be maximized, they show great promise in the treatment of cancer, psychiatric disorders, and other complex diseases. Here we present a review of the epigenetic theory of complex disease and an evaluation of current epigenetic therapies, as well as predictions of the future directions in this expanding field. PMID:17883328

  6. Genetic and epigenetic variations induced by wheat-rye 2R and 5R monosomic addition lines.

    Directory of Open Access Journals (Sweden)

    Shulan Fu

    Full Text Available BACKGROUND: Monosomic alien addition lines (MAALs can easily induce structural variation of chromosomes and have been used in crop breeding; however, it is unclear whether MAALs will induce drastic genetic and epigenetic alterations. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, wheat-rye 2R and 5R MAALs together with their selfed progeny and parental common wheat were investigated through amplified fragment length polymorphism (AFLP and methylation-sensitive amplification polymorphism (MSAP analyses. The MAALs in different generations displayed different genetic variations. Some progeny that only contained 42 wheat chromosomes showed great genetic/epigenetic alterations. Cryptic rye chromatin has introgressed into the wheat genome. However, one of the progeny that contained cryptic rye chromatin did not display outstanding genetic/epigenetic variation. 78 and 49 sequences were cloned from changed AFLP and MSAP bands, respectively. Blastn search indicated that almost half of them showed no significant similarity to known sequences. Retrotransposons were mainly involved in genetic and epigenetic variations. Genetic variations basically affected Gypsy-like retrotransposons, whereas epigenetic alterations affected Copia-like and Gypsy-like retrotransposons equally. Genetic and epigenetic variations seldom affected low-copy coding DNA sequences. CONCLUSIONS/SIGNIFICANCE: The results in the present study provided direct evidence to illustrate that monosomic wheat-rye addition lines could induce different and drastic genetic/epigenetic variations and these variations might not be caused by introgression of rye chromatins into wheat. Therefore, MAALs may be directly used as an effective means to broaden the genetic diversity of common wheat.

  7. Metabotropic Glutamate 2/3 Receptors and Epigenetic Modifications in Psychotic Disorders: A Review.

    Science.gov (United States)

    Matrisciano, Francesco; Panaccione, Isabella; Grayson, Danis R; Nicoletti, Ferdinando; Guidotti, Alessandro

    2016-01-01

    Schizophrenia and Bipolar Disorder are chronic psychiatric disorders, both considered as "major psychosis"; they are thought to share some pathogenetic factors involving a dysfunctional gene x environment interaction. Alterations in the glutamatergic transmission have been suggested to be involved in the pathogenesis of psychosis. Our group developed an epigenetic model of schizophrenia originated by Prenatal Restraint Stress (PRS) paradigm in mice. PRS mice developed some behavioral alterations observed in schizophrenic patients and classic animal models of schizophrenia, i.e. deficits in social interaction, locomotor activity and prepulse inhibition. They also showed specific changes in promoter DNA methylation activity of genes related to schizophrenia such as reelin, BDNF and GAD67, and altered expression and function of mGlu2/3 receptors in the frontal cortex. Interestingly, behavioral and molecular alterations were reversed by treatment with mGlu2/3 agonists. Based on these findings, we speculate that pharmacological modulation of these receptors could have a great impact on early phase treatment of psychosis together with the possibility to modulate specific epigenetic key protein involved in the development of psychosis. In this review, we will discuss in more details the specific features of the PRS mice as a suitable epigenetic model for major psychosis. We will then focus on key proteins of chromatin remodeling machinery as potential target for new pharmacological treatment through the activation of metabotropic glutamate receptors. PMID:26813121

  8. Potential of epigenetic therapies in the management of solid tumors

    International Nuclear Information System (INIS)

    Cancer is a complex disease with both genetic and epigenetic origins. The growing field of epigenetics has contributed to our understanding of oncogenesis and tumor progression, and has allowed the development of novel therapeutic drugs. First-generation epigenetic inhibitor drugs have obtained modest clinical results in two types of hematological malignancy. Second-generation epigenetic inhibitors are in development, and have intrinsically greater selectivity for their molecular targets. Solid tumors are more genetic and epigenetically complex than hematological malignancies, but the transcriptome and epigenome biomarkers have been identified for many of these malignancies. This solid tumor molecular aberration profile may be modified using specific or quasi-specific epidrugs together with conventional and innovative anticancer treatments. In this critical review, we briefly analyze the strategies to select the targeted epigenetic changes, enumerate the second-generation epigenetic inhibitors, and describe the main signs indicating the potential of epigenetic therapies in the management of solid tumors. We also highlight the work of consortia or academic organizations that support the undertaking of human epigenetic therapeutic projects as well as some examples of transcriptome/epigenome profile determination in clinical assessment of cancer patients treated with epidrugs. There is a good chance that epigenetic therapies will be able to be used in patients with solid tumors in the future. This may happen soon through collaboration of diverse scientific groups, making the selection of targeted epigenetic aberration(s) more rapid, the design and probe of drug candidates, accelerating in vitro and in vivo assays, and undertaking new cancer epigenetic-therapy clinical trails

  9. Chromatin resetting mechanisms preventing transgenerational inheritance of epigenetic states

    OpenAIRE

    Iwasaki, Mayumi

    2015-01-01

    Epigenetic regulation can be altered by environmental cues including abiotic and biotic stresses. In most cases, environmentally-induced epigenetic changes are transient, but in some cases they are maintained for extensive periods of time and may even be transmitted to the next generation. However, the underlying mechanisms of transgenerational transmission of environmentally-induced epigenetic states remain largely unknown. Such traits can be adaptive, but also can have negative consequences...

  10. The Structural Determinants behind the Epigenetic Role of Histone Variants

    OpenAIRE

    Manjinder S. Cheema; Juan Ausió

    2015-01-01

    Histone variants are an important part of the histone contribution to chromatin epigenetics. In this review, we describe how the known structural differences of these variants from their canonical histone counterparts impart a chromatin signature ultimately responsible for their epigenetic contribution. In terms of the core histones, H2A histone variants are major players while H3 variant CenH3, with a controversial role in the nucleosome conformation, remains the genuine epigenetic histone v...

  11. Epigenetic therapy in gastrointestinal cancer: the right combination.

    Science.gov (United States)

    Abdelfatah, Eihab; Kerner, Zachary; Nanda, Nainika; Ahuja, Nita

    2016-07-01

    Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer. PMID:27366224

  12. Epigenetic differences after prenatal adversity: the Dutch hunger winter

    OpenAIRE

    Tobi, Elmar Wouter

    2013-01-01

    This thesis is a study on the link between early development and adult health. Studies in animal models indicate that so-called epigenetic marks may be influenced by nutrition during development, changing the expression of genes implicated in disease. Epigenetics may therefore link development and disease. To investigate this hypothesis in humans we studied DNA methylation, a key epigenetic mark, in individuals exposed during early gestation to the Dutch Famine and individuals born growth res...

  13. Dissecting epigenetic silencing complexity in the mouse lung cancer suppressor gene Cadm1.

    Directory of Open Access Journals (Sweden)

    Stella Marie Reamon-Buettner

    Full Text Available Disease-oriented functional analysis of epigenetic factors and their regulatory mechanisms in aberrant silencing is a prerequisite for better diagnostics and therapy. Yet, the precise mechanisms are still unclear and complex, involving the interplay of several effectors including nucleosome positioning, DNA methylation, histone variants and histone modifications. We investigated the epigenetic silencing complexity in the tumor suppressor gene Cadm1 in mouse lung cancer progenitor cell lines, exhibiting promoter hypermethylation associated with transcriptional repression, but mostly unresponsive to demethylating drug treatments. After predicting nucleosome positions and transcription factor binding sites along the Cadm1 promoter, we carried out single-molecule mapping with DNA methyltransferase M.SssI, which revealed in silent promoters high nucleosome occupancy and occlusion of transcription factor binding sites. Furthermore, M.SssI maps of promoters varied within and among the different lung cancer cell lines. Chromatin analysis with micrococcal nuclease also indicated variations in nucleosome positioning to have implications in the binding of transcription factors near nucleosome borders. Chromatin immunoprecipitation showed that histone variants (H2A.Z and H3.3, and opposing histone modification marks (H3K4me3 and H3K27me3 all colocalized in the same nucleosome positions that is reminiscent of epigenetic plasticity in embryonic stem cells. Altogether, epigenetic silencing complexity in the promoter region of Cadm1 is not only defined by DNA hypermethylation, but high nucleosome occupancy, altered nucleosome positioning, and 'bivalent' histone modifications, also likely contributed in the transcriptional repression of this gene in the lung cancer cells. Our results will help define therapeutic intervention strategies using epigenetic drugs in lung cancer.

  14. Early life stress increases stress vulnerability through BDNF gene epigenetic changes in the rat hippocampus.

    Science.gov (United States)

    Seo, Mi Kyoung; Ly, Nguyen Ngoc; Lee, Chan Hong; Cho, Hye Yeon; Choi, Cheol Min; Nhu, Le Hoa; Lee, Jung Goo; Lee, Bong Ju; Kim, Gyung-Mee; Yoon, Bong June; Park, Sung Woo; Kim, Young Hoon

    2016-06-01

    Early life stress (ELS) exerts long-lasting epigenetic influences on the brain and makes an individual susceptible to later depression. It is poorly understood whether ELS and subsequent adult chronic stress modulate epigenetic mechanisms. We examined the epigenetic mechanisms of the BDNF gene in the hippocampus, which may underlie stress vulnerability to postnatal maternal separation (MS) and adult restraint stress (RS). Rat pups were separated from their dams (3 h/day from P1-P21). When the pups reached adulthood (8 weeks old), we introduced RS (2 h/day for 3 weeks) followed by escitalopram treatment. We showed that both the MS and RS groups expressed reduced levels of total and exon IV BDNF mRNA. Furthermore, RS potentiated MS-induced decreases in these expression levels. Similarly, both the MS and RS groups showed decreased levels of acetylated histone H3 and H4 at BDNF promoter IV, and RS exacerbated MS-induced decreases of H3 and H4 acetylation. Both the MS and RS groups had increased MeCP2 levels at BDNF promoter IV, as well as increased HDAC5 mRNA, and the combination of MS and RS exerted a greater effect on these parameters than did RS alone. In the forced swimming test, the immobility time of the MS + RS group was significantly higher than that of the RS group. Additionally, chronic escitalopram treatment recovered these alterations. Our results suggest that postnatal MS and subsequent adult RS modulate epigenetic changes in the BDNF gene, and that these changes may be related to behavioral phenotype. These epigenetic mechanisms are involved in escitalopram action. PMID:26877199

  15. Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity.

    Science.gov (United States)

    Cantor, Joshua P; Iliopoulos, Dimitrios; Rao, Atul S; Druck, Teresa; Semba, Shuho; Han, Shuang-Yin; McCorkell, Kelly A; Lakshman, Thiru V; Collins, Joshua E; Wachsberger, Phyllis; Friedberg, Joseph S; Huebner, Kay

    2007-01-01

    Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and histone deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox, p16(INK4a) and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza-2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm(3)); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16(INKa), Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses. PMID:17019711

  16. 2009 Epigenetics Gordon Research Conference (August 9 - 14, 2009)

    Energy Technology Data Exchange (ETDEWEB)

    Jeanie Lee

    2009-08-14

    Epigenetics refers to the study of heritable changes in genome function that occur without a change in primary DNA sequence. The 2009 Gordon Conference in Epigenetics will feature discussion of various epigenetic phenomena, emerging understanding of their underlying mechanisms, and the growing appreciation that human, animal, and plant health all depend on proper epigenetic control. Special emphasis will be placed on genome-environment interactions particularly as they relate to human disease. Towards improving knowledge of molecular mechanisms, the conference will feature international leaders studying the roles of higher order chromatin structure, noncoding RNA, repeat elements, nuclear organization, and morphogenic evolution. Traditional and new model organisms are selected from plants, fungi, and metazoans.

  17. 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

  18. Study on epigenetic alterations of ore-enclosing sedimentary rocks

    International Nuclear Information System (INIS)

    Epigenetic alterations of sedimentary rocks under effect of exogenous undeground waters of various types: near-surface, ground, stratum, and deep circulation waters, are considered. Association to postsedimentary tectonic structures, confinement of neogenesis to areas of high permeability (porous or crack one), geochemical contradictions between mineral neogenis and facial outlook of deposits, noncoincidence of variability gradient of authigenous mineral associations with variability of primary facial signs of deposits, regular position of mineral formations and ore concentrations in epigenetic mineralogo-geochemical zonation are referred to epigenetic criteria. The complex of epigenetic alterations accompanying mineralization is frequently used as a search sign of uranium deposit of a certain type

  19. Disruptive chemicals, senescence and immortality.

    Science.gov (United States)

    Carnero, Amancio; Blanco-Aparicio, Carmen; Kondoh, Hiroshi; Lleonart, Matilde E; Martinez-Leal, Juan Fernando; Mondello, Chiara; Scovassi, A Ivana; Bisson, William H; Amedei, Amedeo; Roy, Rabindra; Woodrick, Jordan; Colacci, Annamaria; Vaccari, Monica; Raju, Jayadev; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Salem, Hosni K; Memeo, Lorenzo; Forte, Stefano; Singh, Neetu; Hamid, Roslida A; Ryan, Elizabeth P; Brown, Dustin G; Wise, John Pierce; Wise, Sandra S; Yasaei, Hemad

    2015-06-01

    Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes. PMID:26106138

  20. Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum

    Science.gov (United States)

    Lu, Ake T.; Hannon, Eilis; Levine, Morgan E.; Hao, Ke; Crimmins, Eileen M.; Lunnon, Katie; Kozlenkov, Alexey; Mill, Jonathan; Dracheva, Stella; Horvath, Steve

    2016-02-01

    DNA methylation (DNAm) levels lend themselves for defining an epigenetic biomarker of aging known as the `epigenetic clock'. Our genome-wide association study (GWAS) of cerebellar epigenetic age acceleration identifies five significant (Pepigenetic tissue age as endophenotype in GWAS.

  1. Is epigenetics an important link between early life events and adult disease?

    Science.gov (United States)

    Epigenetic mechanisms provide one potential explanation for how environmental influences in early life cause long-term changes in chronic disease susceptibility. Whereas epigenetic dysregulation is increasingly implicated in various rare developmental syndromes and cancer, the role of epigenetics in...

  2. Epigenetic control of cell identity and plasticity

    KAUST Repository

    Orlando, Valerio

    2014-04-02

    The DNA centered dogma for genetic information and cell identity is now evolving into a much more complex and flexible dimension provided by the discovery of the Epigenome. This comprises those chromosome structural and topological components that complement DNA information and contribute to genome functional organization. Current concept is that the Epigenome constitutes the dynamic molecular interface allowing the Genome to interact with the Environment. Exploring how the genome interacts with the environment is a key to fully understand cellular and complex organism mechanisms of adaptation and plasticity. Our work focuses on the role of an essential, specialized group or chromatin associated proteins named Polycomb (PcG) that control maintenance of transcription programs during development and in adult life. In particular PcG proteins exert epigenetic “memory” function by modifying chromosome structures at various levels to maintain gene silencing in particular through cell division. While in the past decade substantial progress was made in understanding PcG mechanisms acting in development and partially during cell cycle, very little is known about their role in adult post-mitotic tissues and more in general the role of the epigenome in adaptation. To this, we studied the role of PcG in the context of mammalian skeletal muscle cell differentiation. We previously reported specific dynamics of PRC2 proteins in myoblasts and myotubes, in particular the dynamics of PcG Histone H3 K27 Methyl Transferases (HMT), EZH2 and EZH1, the latter apparently replacing for EZH2 in differentiated myotubes. Ezh1 protein, although almost identical to Ezh2, shows a weak H3K27 HMT activity and its primary function remains elusive. Recent ChIPseq studies performed in differentiating muscle cells revealed that Ezh1 associates with active and not repressed regulatory regions to control RNA pol II elongation. Since H3K27 tri-methylation levels are virtually steady in non

  3. Epigenetic Effects of Diet on Fruit Fly Lifespan: An Investigation to Teach Epigenetics to Biology Students

    Science.gov (United States)

    Billingsley, James; Carlson, Kimberly A.

    2010-01-01

    Do our genes exclusively control us, or are other factors at play? Epigenetics can provide a means for students to use inquiry-based methods to understand a complex biological concept. Students research and design an experiment testing whether dietary supplements affect the lifespan of Drosophila melanogaster over multiple generations.

  4. Epigenetic estimation of age in humpback whales.

    Science.gov (United States)

    Polanowski, Andrea M; Robbins, Jooke; Chandler, David; Jarman, Simon N

    2014-09-01

    Age is a fundamental aspect of animal ecology, but is difficult to determine in many species. Humpback whales exemplify this as they have a lifespan comparable to humans, mature sexually as early as 4 years and have no reliable visual age indicators after their first year. Current methods for estimating humpback age cannot be applied to all individuals and populations. Assays for human age have recently been developed based on age-induced changes in DNA methylation of specific genes. We used information on age-associated DNA methylation in human and mouse genes to identify homologous gene regions in humpbacks. Humpback skin samples were obtained from individuals with a known year of birth and employed to calibrate relationships between cytosine methylation and age. Seven of 37 cytosines assayed for methylation level in humpback skin had significant age-related profiles. The three most age-informative cytosine markers were selected for a humpback epigenetic age assay. The assay has an R(2) of 0.787 (P = 3.04e-16) and predicts age from skin samples with a standard deviation of 2.991 years. The epigenetic method correctly determined which of parent-offspring pairs is the parent in more than 93% of cases. To demonstrate the potential of this technique, we constructed the first modern age profile of humpback whales off eastern Australia and compared the results to population structure 5 decades earlier. This is the first epigenetic age estimation method for a wild animal species and the approach we took for developing it can be applied to many other nonmodel organisms. PMID:24606053

  5. Epigenetic regulation of non-lymphoid cells by Bisphenol-A, a model endocrine disrupter: Potential Implications for Immunoregulation

    Directory of Open Access Journals (Sweden)

    Deena eKhan

    2015-06-01

    Full Text Available Endocrine disrupting chemicals (EDC abound in the environment since many compounds are released from chemical, agricultural, pharmaceutical and consumer product industries. Many of the EDCs such as Bisphenol A (BPA have estrogenic activity or interfere with endogenous sex hormones. Experimental studies have reported a positive correlation of BPA with reproductive toxicity, altered growth and immune dysregulation. Although the precise relevance of these studies to the environmental levels is unclear, nevertheless, their potential health implications remain a concern. One possible mechanism by which BPA can alter genes is by regulating epigenetics, including microRNA, alteration of methylation and histone acetylation. There is now wealth of information on BPA effects on non-lymphoid cells and by comparison, paucity of data on effects of BPA on the immune system. In this mini review, we will highlight BPA regulation of estrogen receptor-mediated immune cell functions and in different inflammatory conditions. In addition, BPA-mediated epigenetic regulation of non-lymphoid cells is emphasized. We recognize that most of these studies are on non-lymphoid cells, and given that BPA also affects the immune system, it is plausible that BPA could have similar epigenetic regulation in immune cells. It is hoped that this review will stimulate studies in this area to ascertain whether or not BPA epigenetically regulates the cells of the immune system.

  6. Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise.

    Science.gov (United States)

    Cosín-Tomás, Marta; Alvarez-López, María J; Sanchez-Roige, Sandra; Lalanza, Jaume F; Bayod, Sergi; Sanfeliu, Coral; Pallàs, Merce; Escorihuela, Rosa M; Kaliman, Perla

    2014-01-01

    The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by 8 weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene expression by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging. PMID:24688469

  7. Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise

    Directory of Open Access Journals (Sweden)

    Marta eCosín-Tomás

    2014-03-01

    Full Text Available The senescence-accelerated SAMP8 mouse model displays features of cognitive decline and Alzheimer's disease. With the purpose of identifying potential epigenetic markers involved in aging and neurodegeneration, here we analyzed the expression of 84 mature miRNAs, the expression of histone-acetylation regulatory genes and the global histone acetylation in the hippocampus of 8-month-old SAMP8 mice, using SAMR1 mice as control. We also examined the modulation of these parameters by eight weeks of voluntary exercise. Twenty-one miRNAs were differentially expressed between sedentary SAMP8 and SAMR1 mice and seven miRNAs were responsive to exercise in both strains. SAMP8 mice showed alterations in genes involved in protein acetylation homeostasis such as Sirt1 and Hdac6 and modulation of Hdac3 and Hdac5 gene expression by exercise. Global histone H3 acetylation levels were reduced in SAMP8 compared with SAMR1 mice and reached control levels in response to exercise. In sum, data presented here provide new candidate epigenetic markers for aging and neurodegeneration and suggest that exercise training may prevent or delay some epigenetic alterations associated with accelerated aging.

  8. Epigenetic modulation of host: new insights into immune evasion by viruse

    Indian Academy of Sciences (India)

    Dwaipayan Adhya; Anirban Basu

    2010-12-01

    Viruses have evolved with their hosts, which include all living species. This has been partly responsible for the development of highly advanced immune systems in the hosts. However, viruses too have evolved ways to regulate and evade the host’s immune defence. In addition to mutational mechanisms that viruses employ to mimic the host genome and undergo latency to evade the host’s recognition of the pathogen, they have also developed epigenetic mechanisms by which they can render the host’s immune responses inactive to their antigens. The epigenetic regulation of gene expression is intrinsically active inside the host and is involved in regulating gene expression and cellular differentiation. Viral immune evasion strategies are an area of major concern in modern biomedical research. Immune evasion strategies may involve interference with the host antigen presentation machinery or host immune gene expression capabilities, and viruses, in these manners, introduce and propagate infection. The aim of this review is to elucidate the various epigenetic changes that viruses are capable of bringing about in their host in order to enhance their own survivability and pathogenesis.

  9. Evidence for epigenetic alterations in Turner syndrome opens up feasibility of new pharmaceutical interventions.

    Science.gov (United States)

    Rajpathak, Shriram N; Deobagkar, Deepti D

    2014-01-01

    DNA methylation is an important regulatory component which influences phenotypes by modulating gene expression. Changes in DNA methylation may lead to altered phenotypes and ability of an organism to respond to stress leading to subsequent manifestation of life style diseases, cancer, etc. The human X chromosome represents a classical model for epigenetic processes governing differential regulation of homologous chromosomes. X monosomy (45, XO) leads to Turner's syndrome in human with mild to severe phenotypes. Using a novel cDNA based high throughput approach of assessing genome wide methylation; we have examined the methylation landscape in human fibroblasts in 45, XO and 46, XX individuals. We report here that as expected methylation of X linked genes is different in these two situations. It was observed that methylation of several autosomal genes is also affected in this X monosomy state. Genes involved in bone remodeling, glucose sensitivity and ovarian function appear to be altered in addition to genes involved in epigenetic regulatory processes. This opens up interesting possibility of misregulation of DNA methylation in the X monosomy state resulting in altered gene expression and altered phenotypes. This may be one of the reasons for the variance, differential severity and penetrance in case of Turner's syndrome. We propose that a systematic analysis of the molecular genetic mechanisms governing this epigenetic regulation will open up new therapeutic interventions which will certainly help in reducing severity of the disease and help in better management of X monosomy (Turner's syndrome). PMID:23888970

  10. Increased apomixis expression concurrent with genetic and epigenetic variation in a newly synthesized Eragrostis curvula polyploid

    Science.gov (United States)

    Zappacosta, Diego C.; Ochogavía, Ana C.; Rodrigo, Juan M.; Romero, José R.; Meier, Mauro S.; Garbus, Ingrid; Pessino, Silvina C.; Echenique, Viviana C.

    2014-04-01

    Eragrostis curvula includes biotypes reproducing through obligate and facultative apomixis or, rarely, full sexuality. We previously generated a ``tetraploid-dihaploid-tetraploid'' series of plants consisting of a tetraploid apomictic plant (T), a sexual dihaploid plant (D) and a tetraploid artificial colchiploid (C). Initially, plant C was nearly 100% sexual. However, its capacity to form non-reduced embryo sacs dramatically increased over a four year period (2003-2007) to reach levels of 85-90%. Here, we confirmed high rates of apomixis in plant C, and used AFLPs and MSAPs to characterize the genetic and epigenetic variation observed in this plant in 2007 as compared to 2003. Of the polymorphic sequences, some had no coding potential whereas others were homologous to retrotransposons and/or protein-coding-like sequences. Our results suggest that in this particular plant system increased apomixis expression is concurrent with genetic and epigenetic modifications, possibly involving transposable elements.

  11. Epigenetic memory of PTGS-induced epialelles of tobacco transgenes

    Czech Academy of Sciences Publication Activity Database

    Lunerová Bedřichová, Jana; Bleys, A.; Fojtová, Miloslava; Crhák Khaitová, Lucie; Depicker, A.; Kovařík, Aleš

    Heidelberg, 2007. s. 155-155. [EMBO Conference on Chromatin and Epigenetics. 03.05.2007-06.05.2007, Heidelberg] R&D Projects: GA MŠk(CZ) LC06004; GA AV ČR(CZ) IAA600040611 Institutional research plan: CEZ:AV0Z50040507 Keywords : DNA methylation * epigenetic inheritance * silencing Subject RIV: BO - Biophysics

  12. Analysis of epigenetic modifications of DNA in human cells

    DEFF Research Database (Denmark)

    Kristensen, Lasse Sommer; Treppendahl, Marianne Bach; Grønbæk, Kirsten

    2013-01-01

    Epigenetics, the study of somatically heritable changes in gene expression not related to changes in the DNA sequence, is a rapidly expanding research field that plays important roles in healthy as well as in diseased cells. DNA methylation and hydroxymethylation are epigenetic modifications found...

  13. Epigenetic Contributions to Cognitive Aging: Disentangling Mindspan and Lifespan

    Science.gov (United States)

    Spiegel, Amy M.; Sewal, Angila S.; Rapp, Peter R.

    2014-01-01

    Epigenetic modifications of chromatin structure provide a mechanistic interface for gene-environment interactions that impact the individualization of health trajectories across the lifespan. A growing body of research indicates that dysfunctional epigenetic regulation contributes to poor cognitive outcomes among aged populations. Here we review…

  14. Epigenetics in adipose tissue, obesity, weight loss and diabetes

    Science.gov (United States)

    Given the role that the diet and other environmental factors play in the development of obesity and type 2 diabetes, the implication of different epigenetic processes is being investigated. Although it is well known that the environmental factors can cause cell type-dependent epigenetic changes, inc...

  15. Nutritional influences on epigenetics and age-related disease

    Science.gov (United States)

    Nutritional epigenetics has emerged as a novel mechanism underlying gene–diet interactions, further elucidating the modulatory role of nutrition in aging and age-related disease development. Epigenetics is defined as a heritable modification to the DNA that regulates chromosome architecture and modu...

  16. Ontogeny and Phylogeny from an Epigenetic Point of View.

    Science.gov (United States)

    Lovtrup, Soren

    1984-01-01

    The correlation between ontogeny and phylogeny is analyzed through the discussion of four theories on the reality, history, epigenetic, and ecological aspects of the mechanism of evolution. Also discussed are historical and creative aspects of evolution and three epigenetic mechanisms instantiated in the case of the amphibian embryo. (Author/RH)

  17. The epigenetic landscape of mammary gland development and functional differentiation

    Science.gov (United States)

    Most of the development and functional differentiation in the mammary gland occur after birth. Epigenetics is defined as the stable alterations in gene expression potential that arise during development and proliferation. Epigenetic changes are mediated at the biochemical level by the chromatin conf...

  18. Epigenetic maturation in colonic mucosa continues beyond infancy in mice.

    Science.gov (United States)

    Monozygotic twin and other epidemiologic studies indicate that epigenetic processes may play an important role in the pathogenesis of inflammatory bowel diseases that commonly affect the colonic mucosa. The peak onset of these disorders in young adulthood, suggests that epigenetic changes normally o...

  19. Epigenetic differences after prenatal adversity : the Dutch hunger winter

    NARCIS (Netherlands)

    Tobi, Elmar Wouter

    2013-01-01

    This thesis is a study on the link between early development and adult health. Studies in animal models indicate that so-called epigenetic marks may be influenced by nutrition during development, changing the expression of genes implicated in disease. Epigenetics may therefore link development and d

  20. Epigenetics in non-small cell lung cancer: from basics to therapeutics

    Science.gov (United States)

    Ansari, Junaid; El-Osta, Hazem

    2016-01-01

    Lung cancer remains the number one cause of cancer-related deaths worldwide with 221,200 estimated new cases and 158,040 estimated deaths in 2015. Approximately 80% of cases are non-small cell lung cancer (NSCLC). The diagnosis is usually made at an advanced stage where the prognosis is poor and therapeutic options are limited. The evolution of lung cancer is a multistep process involving genetic, epigenetic, and environmental factor interactions that result in the dysregulation of key oncogenes and tumor suppressor genes, culminating in activation of cancer-related signaling pathways. The past decade has witnessed the discovery of multiple molecular aberrations that drive lung cancer growth, among which are epidermal growth factor receptor (EGFR) mutations and translocations involving the anaplastic lymphoma kinase (ALK) gene. This has translated into therapeutic agent developments that target these molecular alterations. The absence of targetable mutations in 50% of NSCLC cases and targeted therapy resistance development underscores the importance for developing alternative therapeutic strategies for treating lung cancer. Among these strategies, pharmacologic modulation of the epigenome has been used to treat lung cancer. Epigenetics approaches may circumvent the problem of tumor heterogeneity by affecting the expression of multiple tumor suppression genes (TSGs), halting tumor growth and survival. Moreover, it may be effective for tumors that are not driven by currently recognized druggable mutations. This review summarizes the molecular pathology of lung cancer epigenetic aberrations and discusses current efforts to target the epigenome with different pharmacological approaches. Our main focus will be on hypomethylating agents, histone deacetylase (HDAC) inhibitors, microRNA modulations, and the role of novel epigenetic biomarkers. Last, we will address the challenges that face this old-new strategy in treating lung cancer.