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Sample records for chemicals involves epigenetic

  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. Chemical genetics approaches for selective intervention in epigenetics.

    Science.gov (United States)

    Runcie, Andrew C; Chan, Kwok-Ho; Zengerle, Michael; Ciulli, Alessio

    2016-08-01

    Chemical genetics is the use of biologically active small molecules (chemical probes) to investigate the functions of gene products, through the modulation of protein activity. Recent years have seen significant progress in the application of chemical genetics to study epigenetics, following the development of new chemical probes, a growing appreciation of the role of epigenetics in disease and a recognition of the need and utility of high-quality, cell-active chemical probes. In this review, we single out the bromodomain reader domains as a prime example of both the success, and challenges facing chemical genetics. The difficulty in generating single-target selectivity has long been a thorn in the side of chemical genetics, however, recent developments in advanced forms of chemical genetics promise to bypass this, and other, limitations. The 'bump-and-hole' approach has now been used to probe - for the first time - the BET bromodomain subfamily with single-target selectivity and may be applicable to other epigenetic domains. Meanwhile, PROTAC compounds have been shown to be significantly more efficacious than standard domain inhibitors, and have the potential to enhance target selectivity.

  4. 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

  5. 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.

  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. 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...

  8. 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

  9. 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.

  10. In planta assays involving epigenetically silenced genes reveal inhibition of cytosine methylation by genistein

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    Arase Sachiko

    2012-03-01

    Full Text Available Abstract Background Cytosine methylation is involved in epigenetic control of gene expression in a wide range of organisms. An increasing number of examples indicate that changing the frequency of cytosine methylation in the genome is a feasible tool to engineer novel traits in plants. Although demethylating effects of compounds have been analyzed in human cultured cells in terms of suppressing cancer, their effect in plant cells has not been analyzed extensively. Here, we developed in planta assay systems to detect inhibition of cytosine methylation using plants that contain a transgene transcriptionally silenced by an epigenetic mechanism. Results Seeds of two transgenic plants were used: a petunia line that has been identified as a revertant of the co-suppression of the chalcone synthase-A (CHS-A gene and contains CHS-A transgenes whose transcription is repressed; Nicotiana benthamiana plants that contain the green fluorescent protein (GFP reporter gene whose transcription is repressed through virus-induced transcriptional gene silencing. Seeds of these plants were sown on a medium that contained a demethylating agent, either 5-azacytidine or trichostatin A, and the restoration of the transcriptionally active state of the transgene was detected in seedlings. Using these systems, we found that genistein, a major isoflavonoid compound, inhibits cytosine methylation, thus restoring transgene transcription. Genistein also restored the transcription of an epigenetically silenced endogenous gene in Arabidopsis plants. Conclusions Our assay systems allowed us to assess the inhibition of cytosine methylation, in particular of maintenance of methylation, by compounds in plant cells. These results suggest a novel role of flavonoids in plant cells and that genistein is useful for modifying the epigenetic state of plant genomes.

  11. Human intelligence and polymorphisms in the DNA methyltransferase genes involved in epigenetic marking.

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    Paul Haggarty

    Full Text Available Epigenetic mechanisms have been implicated in syndromes associated with mental impairment but little is known about the role of epigenetics in determining the normal variation in human intelligence. We measured polymorphisms in four DNA methyltransferases (DNMT1, DNMT3A, DNMT3B and DNMT3L involved in epigenetic marking and related these to childhood and adult general intelligence in a population (n = 1542 consisting of two Scottish cohorts born in 1936 and residing in Lothian (n = 1075 or Aberdeen (n = 467. All subjects had taken the same test of intelligence at age 11yrs. The Lothian cohort took the test again at age 70yrs. The minor T allele of DNMT3L SNP 11330C>T (rs7354779 allele was associated with a higher standardised childhood intelligence score; greatest effect in the dominant analysis but also significant in the additive model (coefficient = 1.40(additive; 95%CI 0.22,2.59; p = 0.020 and 1.99(dominant; 95%CI 0.55,3.43; p = 0.007. The DNMT3L C allele was associated with an increased risk of being below average intelligence (OR 1.25(additive; 95%CI 1.05,1.51; p = 0.011 and OR 1.37(dominant; 95%CI 1.11,1.68; p = 0.003, and being in the lowest 40(th (p(additive = 0.009; p(dominant = 0.002 and lowest 30(th (p(additive = 0.004; p(dominant = 0.002 centiles for intelligence. After Bonferroni correction for the number variants tested the link between DNMT3L 11330C>T and childhood intelligence remained significant by linear regression and centile analysis; only the additive regression model was borderline significant. Adult intelligence was similarly linked to the DNMT3L variant but this analysis was limited by the numbers studied and nature of the test and the association was not significant after Bonferroni correction. We believe that the role of epigenetics in the normal variation in human intelligence merits further study and that this novel finding should be tested in other cohorts.

  12. 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

  13. 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.

  14. RPL1, a Gene Involved in Epigenetic Processes Regulates Phenotypic Plasticity in Rice

    Institute of Scientific and Technical Information of China (English)

    Cui-Cui Zhang; Wen-Ya Yuan; Qi-Fa Zhang

    2012-01-01

    Organisms can adjust their phenotype in response to changing environmental conditions.This phenomenon is termed phenotypic plasticity.Despite its ubiquitous occurrence,there has been very little study on the molecular mechanism of phenotypic plasticity.In this study,we isolated a rice (Oryza sativa L.) mutant,rice plasticity 1 (rpl1),that displayed increased environment-dependent phenotypic variations.RPL1 was expressed in all tissues examined.The protein was localized in the nucleus and its distribution in the nucleus overlapped with heterochromatin.The rpl1 mutation led to an increase in DNA methylation on repetitive sequences and a decrease in overall histone acetylation.In addition,the mutation affected responses of the rice plant to phytohormones such as brassinosteroid,gibberellin,and cytokinin.Analysis of the putative rice brassinosteroid receptor OsBRI1,a key hormone signaling gene,indicated that RPL1 may be involved in the regulation of epigenomic modification of the gene.These data suggest that RPL1 regulated phenotypic plasticity likely through its involvement in epigenetic processes affecting responses of the plant to phytohormones.

  15. 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.

  16. Incorporating transgenerational testing and epigenetic mechanisms into chemical testing and risk assessment: A survey of transgenerational responses in environmental chemical studies

    Science.gov (United States)

    A number of environmental chemicals have been shown to alter markers of epigenetic change. Some published multi-generation rodent studies have identified effects on F2 and greater generations after chemical exposures solely to F0 dams, but were not focused on chemical safety. We ...

  17. [Epigenetic heredity in mice: involvement of RNA and miRNas.].

    Science.gov (United States)

    Rassoulzadegan, Minoo; Grandjean, Valérie; Gounon, Pierre; Cuzin, François

    2007-01-01

    By contrast with a wide definition of the 'epigenetic variation', including all changes in gene expression that do not result from alteration of the gene structure, a more restricted class had been defined, initially in plants, under the name 'paramutation'. It corresponds to epigenetic modifications distinct from the regulatory interactions of the cell differentiation pathways, mitotically stable and sexually transmitted with non-Mendelian patterns. This class of epigenetic changes appeared for some time restricted to the plant world, but examples progressively accumulated of epigenetic inheritance in organisms ranging from mice to humans. Occurrence of paramutation in the mouse and possible mechanisms were then established in the paradigmatic case of a mutant phenotype maintained and hereditarily transmitted by wild type homozygotes. Together with recent findings in plants indicative of a necessary step of RNA amplification in the reference maize paramutation, the mouse studies point to a new role of RNA, as an inducer and hereditary determinant of epigenetic variation. Given the known presence of a wide range of RNAs in human spermatozoa, as well as a number of unexplained cases of familial disease predisposition and transgenerational maintenance, speculations can be extended to possible roles of RNA-mediated inheritance in human biology and pathology. PMID:18533100

  18. 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.

  19. 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

  20. 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

  1. 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 ...

  2. Epigenetic rejuvenation.

    Science.gov (United States)

    Manukyan, Maria; Singh, Prim B

    2012-05-01

    Induced pluripotent stem (iPS) cells have provided a rational means of obtaining histo-compatible tissues for 'patient-specific' regenerative therapies (Hanna et al. 2010; Yamanaka & Blau 2010). Despite the obvious potential of iPS cell-based therapies, there are certain problems that must be overcome before these therapies can become safe and routine (Ohi et al. 2011; Pera 2011). As an alternative, we have recently explored the possibility of using 'epigenetic rejuvenation', where the specialized functions of an old cell are rejuvenated in the absence of any change in its differentiated state (Singh & Zacouto 2010). The mechanism(s) that underpin 'epigenetic rejuvenation' are unknown and here we discuss model systems, using key epigenetic modifiers, which might shed light on the processes involved. Epigenetic rejuvenation has advantages over iPS cell techniques that are currently being pursued. First, the genetic and epigenetic abnormalities that arise through the cycle of dedifferentiation of somatic cells to iPS cells followed by redifferentiation of iPS cells into the desired cell type are avoided (Gore et al. 2011; Hussein et al. 2011; Pera 2011): epigenetic rejuvenation does not require passage through the de-/redifferentiation cycle. Second, because the aim of epigenetic rejuvenation is to ensure that the differentiated cell type retains its specialized function it makes redundant the question of transcriptional memory that is inimical to iPS cell-based therapies (Ohi et al. 2011). Third, to produce unrelated cell types using the iPS technology takes a long time, around three weeks, whereas epigenetic rejuvenation of old cells will take only a matter of days. Epigenetic rejuvenation provides the most safe, rapid and cheap route to successful regenerative medicine. PMID:22487104

  3. 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

  4. 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...

  5. Epigenetic targets of polyphenols in cancer.

    Science.gov (United States)

    Yang, Pinglin; He, Xijing; Malhotra, Anshoo

    2014-01-01

    Interest in dietary polyphenols has recently increased greatly owing to their antioxidant capacity and their possible beneficial implications in various pathological states, including cancer. Polyphenols are a group of chemicals found in many fruits, vegetables, and plants and have the ability to remove free radicals from the body. In the last 2 decades, the numbers of reports on the potential health benefits of polyphenols have increased. This review provides the available scientific data that justify importance of polyphenols in correlation with epigenetics to fight against carcinogenesis. Epigenetics involves genetic control by mechanisms other than DNA sequence. These epigenetic mechanisms have ability to switch on or off various important genes influencing the process of cancer. Furthermore, due to the reversible nature of these epigenetic mechanisms, they are influenced by a variety of dietary polyphenols. This review focuses on the dietary polyphenols that significantly affect these epigenetic mechanisms to mitigate carcinogenesis.

  6. 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.

  7. 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.

  8. 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

  9. Detection of epigenetic aberrations in the development of hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Yujing

    2015-01-01

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Hepatocarcinogenesis is a complex, multistep process. It is now recognized that HCC is a both genetic and epigenetic disease; genetic and epigenetic components cooperate at all stages of hepatocarcinogenesis. Epigenetic changes involve aberrant DNA methylation, posttranslational histone modifications and aberrant expression of microRNAs all of which can affect the expression of oncogenes, tumor suppressor genes and other tumor-related genes and alter the pathways in cancer development. Several risk factors for HCC, including hepatitis B and C virus infections and exposure to the chemical carcinogen aflatoxin B1 have been found to influence epigenetic changes. Their interactions could play an important role in the initiation and progression of HCC. Discovery and detection of biomarkers for epigenetic changes is a promising area for early diagnosis and risk prediction of HCC.

  10. 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

  11. Epigenetics and aging.

    Science.gov (United States)

    Pal, Sangita; Tyler, Jessica K

    2016-07-01

    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

  12. 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

  13. 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

  14. 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...

  15. 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...

  16. 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

  17. 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...

  18. Epigenetic targets of arsenic: emphasis on epigenetic modifications during carcinogenesis.

    Science.gov (United States)

    Roy, Ram Vinod; Son, Young-Ok; Pratheeshkumar, Poyil; Wang, Lei; Hitron, John Andrew; Divya, Sasidharan Padmaja; D, Rakesh; Kim, Donghern; Yin, Yuanqin; Zhang, Zhuo; Shi, Xianglin

    2015-01-01

    DNA methylation and histone modification promote opening and closure of chromatin structure, which affects gene expression without altering the DNA sequence. Epigenetic markers regulate the dynamic nature of chromatin structure at different levels: DNA, histone, noncoding RNAs, as well as the higher-order chromatin structure. Accumulating evidence strongly suggests that arsenic-induced carcinogenesis involves frequent changes in the epigenetic marker. However, progress in identifying arsenic-induced epigenetic changes has already been made using genome-wide approaches; the biological significance of these epigenetic changes remains unknown. Moreover, arsenic-induced changes in the chromatin state alter gene expression through the epigenetic mechanism. The current review provides a summary of recent literature regarding epigenetic changes caused by arsenic in carcinogenesis. We highlight the transgenerational studies needed to explicate the biological significance and toxicity of arsenic over a broad spectrum.

  19. 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...

  20. 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.

  1. Epigenetics of Obesity.

    Science.gov (United States)

    Lopomo, A; Burgio, E; Migliore, L

    2016-01-01

    Obesity is a metabolic disease, which is becoming an epidemic health problem: it has been recently defined in terms of Global Pandemic. Over the years, the approaches through family, twins and adoption studies led to the identification of some causal genes in monogenic forms of obesity but the origins of the pandemic of obesity cannot be considered essentially due to genetic factors, because human genome is not likely to change in just a few years. Epigenetic studies have offered in recent years valuable tools for the understanding of the worldwide spread of the pandemic of obesity. The involvement of epigenetic modifications-DNA methylation, histone tails, and miRNAs modifications-in the development of obesity is more and more evident. In the epigenetic literature, there are evidences that the entire embryo-fetal and perinatal period of development plays a key role in the programming of all human organs and tissues. Therefore, the molecular mechanisms involved in the epigenetic programming require a new and general pathogenic paradigm, the Developmental Origins of Health and Disease theory, to explain the current epidemiological transition, that is, the worldwide increase of chronic, degenerative, and inflammatory diseases such as obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. Obesity and its related complications are more and more associated with environmental pollutants (obesogens), gut microbiota modifications and unbalanced food intake, which can induce, through epigenetic mechanisms, weight gain, and altered metabolic consequences. PMID:27288829

  2. Long-range epigenetic silencing of chromosome 5q31 protocadherins is involved in early and late stages of colorectal tumorigenesis through modulation of oncogenic pathways

    DEFF Research Database (Denmark)

    Dallosso, A R; Øster, Bodil; Greenhough, A;

    2012-01-01

    Loss of tumour suppressor gene function can occur as a result of epigenetic silencing of large chromosomal regions, referred to as long-range epigenetic silencing (LRES), and genome-wide analyses have revealed that LRES is present in many cancer types. Here we utilize Illumina Beadchip methylatio...

  3. 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...

  4. Common non-epigenetic drugs as epigenetic modulators.

    Science.gov (United States)

    Lötsch, Jörn; Schneider, Gisbert; Reker, Daniel; Parnham, Michael J; Schneider, Petra; Geisslinger, Gerd; Doehring, Alexandra

    2013-12-01

    Epigenetic effects are exerted by a variety of factors and evidence increases that common drugs such as opioids, cannabinoids, valproic acid, or cytostatics may induce alterations in DNA methylation patterns or histone conformations. These effects occur via chemical structural interactions with epigenetic enzymes, through interactions with DNA repair mechanisms. Computational predictions indicate that one-twentieth of all drugs might potentially interact with human histone deacetylase, which was prospectively experimentally verified for the compound with the highest predicted interaction probability. These epigenetic effects add to wanted and unwanted drug effects, contributing to mechanisms of drug resistance or disease-related and unrelated phenotypes. Because epigenetic changes might be transmitted to offspring, the need for reliable and cost-effective epigenetic screening tools becomes acute.

  5. Epigenetic regulation of the mammalian cell.

    Directory of Open Access Journals (Sweden)

    Keith Baverstock

    Full Text Available BACKGROUND: Understanding how mammalian cells are regulated epigenetically to express phenotype is a priority. The cellular phenotypic transition, induced by ionising radiation, from a normal cell to the genomic instability phenotype, where the ability to replicate the genotype accurately is compromised, illustrates important features of epigenetic regulation. Based on this phenomenon and earlier work we propose a model to describe the mammalian cell as a self assembled open system operating in an environment that includes its genotype, neighbouring cells and beyond. Phenotype is represented by high dimensional attractors, evolutionarily conditioned for stability and robustness and contingent on rules of engagement between gene products encoded in the genetic network. METHODOLOGY/FINDINGS: We describe how this system functions and note the indeterminacy and fluidity of its internal workings which place it in the logical reasoning framework of predicative logic. We find that the hypothesis is supported by evidence from cell and molecular biology. CONCLUSIONS: Epigenetic regulation and memory are fundamentally physical, as opposed to chemical, processes and the transition to genomic instability is an important feature of mammalian cells with probable fundamental relevance to speciation and carcinogenesis. A source of evolutionarily selectable variation, in terms of the rules of engagement between gene products, is seen as more likely to have greater prominence than genetic variation in an evolutionary context. As this epigenetic variation is based on attractor states phenotypic changes are not gradual; a phenotypic transition can involve the changed contribution of several gene products in a single step.

  6. Bisphenol A Effects on Mammalian Oogenesis and Epigenetic Integrity of Oocytes: A Case Study Exploring Risks of Endocrine Disrupting Chemicals

    Directory of Open Access Journals (Sweden)

    Ursula Eichenlaub-Ritter

    2015-01-01

    Full Text Available Bisphenol A (BPA, originally developed as a synthetic oestrogen, is nowadays extensively used in the production of polymeric plastics. Under harsh conditions, these plastics may release BPA, which then can leach into the environment. Detectable concentrations of BPA have been measured in most analysed samples of human serum, plasma, or urine, as well as in follicular fluid, foetal serum, and amniotic fluid. Here we summarize the evidence about adverse BPA effects on the genetic and epigenetic integrity of mammalian oocytes. We conclude that increasing evidence supports the notion that low BPA concentrations adversely affect the epigenome of mammalian female germ cells, with functional consequences on gene expression, chromosome dynamics in meiosis, and oocyte development. Specific time windows, during which profound chromatin remodelling occurs and maternal imprints are established or protected, appear particularly vulnerable to epigenetic deregulation by BPA. Transgenerational effects have been also observed in the offspring of BPA-treated rodents, although the epigenetic mechanisms of inheritance still need to be clarified. The relevance of these findings for human health protection still needs to be fully assessed, but they warrant further investigation in both experimental models and humans.

  7. Epigenetic regulation in mammalian preimplantation embryo development

    Directory of Open Access Journals (Sweden)

    Shi Lingjun

    2009-06-01

    Full Text Available Abstract Preimplantation embryo development involves four stages: fertilization, cell cleavage, morula and blastocyst formation. During these stages, maternal and zygotic epigenetic factors play crucial roles. The gene expression profile is changed dramatically, chromatin is modified and core histone elements undergo significant changes. Each preimplantation embryo stage has its own characteristic epigenetic profile, consistent with the acquisition of the capacity to support development. Moreover, histone modifications such as methylation and acetylation as well as other epigenetic events can act as regulatory switches of gene transcription. Because the epigenetic profile is largely related to differentiation, epigenetic dysfunction can give rise to developmental abnormalities. Thus, epigenetic profiling of the embryo is of pivotal importance clinically. Given the importance of these aspects, this review will mainly focus on the epigenetic profile during preimplantation embryo development, as well as interactions between epigenetic and genetic regulation in these early developmental stages.

  8. 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

  9. 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

  10. 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.

  11. Epigenetics and Breast Cancers

    Directory of Open Access Journals (Sweden)

    An T. Vo

    2012-01-01

    Full Text Available Several of the active compounds in foods, poisons, drugs, and industrial chemicals may, by epigenetic mechanisms, increase or decrease the risk of breast cancers. Enzymes that are involved in DNA methylation and histone modifications have been shown to be altered in several types of breast and other cancers resulting in abnormal patterns of methylation and/or acetylation. Hypermethylation at the CpG islands found in estrogen response element (ERE promoters occurs in conjunction with ligand-bonded alpha subunit estrogen receptor (Erα dimers wherein the ligand ERα dimer complex acts as a transcription factor and binds to the ERE promoter. Ligands could be 17-β-estradiol (E2, phytoestrogens, heterocyclic amines, and many other identified food additives and heavy metals. The dimer recruits DNA methyltransferases which catalyze the transfer of methyl groups from S-adenosyl-L-methionine (SAM to 5′-cytosine on CpG islands. Other enzymes are recruited to the region by ligand-ERα dimers which activate DNA demethylases to act simultaneously to increase gene expression of protooncogenes and growth-promoting genes. Ligand-ERα dimers also recruit histone acetyltransferase to the ERE promoter region. Histone demethylases such as JMJD2B and histone methyltransferases are enzymes which demethylate lysine residues on histones H3 and/or H4. This makes the chromatin accessible for transcription factors and enzymes.

  12. An update on the epigenetics of glioblastomas.

    Science.gov (United States)

    Ferreira, Wallax Augusto Silva; Pinheiro, Danilo do Rosário; Costa Junior, Carlos Antonio da; Rodrigues-Antunes, Symara; Araújo, Mariana Diniz; Leão Barros, Mariceli Baia; Teixeira, Adriana Corrêa de Souza; Faro, Thamirys Aline Silva; Burbano, Rommel Rodriguez; Oliveira, Edivaldo Herculano Correa de; Harada, Maria Lúcia; Borges, Bárbara do Nascimento

    2016-09-01

    Glioblastomas, also known as glioblastoma multiforme (GBM), are the most aggressive and malignant type of primary brain tumor in adults, exhibiting notable variability at the histopathological, genetic and epigenetic levels. Recently, epigenetic alterations have emerged as a common hallmark of many tumors, including GBM. Considering that a deeper understanding of the epigenetic modifications that occur in GBM may increase the knowledge regarding the tumorigenesis, progression and recurrence of this disease, in this review we discuss the recent major advances in GBM epigenetics research involving histone modification, glioblastoma stem cells, DNA methylation, noncoding RNAs expression, including their main alterations and the use of epigenetic therapy as a valid option for GBM treatment. PMID:27585647

  13. 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.

  14. A mass casualty incident involving children and chemical decontamination.

    Science.gov (United States)

    Timm, Nathan; Reeves, Scott

    2007-01-01

    Mass casualty incidents involving contaminated children are a rare but ever-present possibility. In this article we outline one such event that resulted in 53 pediatric patients and 3 adults presenting to the emergency department of a children's hospital for decontamination and treatment. We pay special attention to the training that allowed this responses to occur. We also outline the institutional response with emphasis on incident command, communication, and resource utilization. Specific lessons learned are explored in detail. Finally, we set forth a series of recommendations to assist other institutions should they be called upon to care for and decontaminate pediatric patients.

  15. Clinical implications of epigenetic alterations in human thoracic malignancies: epigenetic alterations in lung cancer.

    Science.gov (United States)

    Shinjo, Keiko; Kondo, Yutaka

    2012-01-01

    Besides known genetic aberrations, epigenetic alterations have emerged as common hallmarks of many cancer types, including lung cancer. Epigenetics is a process involved in gene regulation, mediated via DNA methylation, histone modification, chromatin remodeling, and functional noncoding RNAs, which influences the accessibility of the underlying DNA to transcriptional regulatory factors that activate or repress expression. Studies have shown that epigenetic dysregulation is associated with multiple steps during carcinogenesis. Since epigenetic therapy is now in clinical use in hematopoietic diseases and undergoing trials for lung cancer, a better understanding of epigenetic abnormalities is desired. Recent technologies for high-throughput genome-wide analyses for epigenetic modifications are promising and potent tools for understanding the global dysregulation of cancer epigenetics. In this chapter, studies of epigenetic abnormality and its clinical implication in lung cancers are discussed.

  16. 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....

  17. Epigenetic Mechanisms in Penile Carcinoma

    Directory of Open Access Journals (Sweden)

    Hellen Kuasne

    2013-05-01

    Full Text Available 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 in specific genes in a limited number of cases. This review aims to provide an overview of the current knowledge of the epigenetic alterations in PeCa and the promising results in this field. The identification of epigenetically altered genes in PeCa is an important step in understanding the mechanisms involved in this unexplored disease.

  18. Animal models in epigenetic research: institutional animal care and use committee considerations across the lifespan.

    Science.gov (United States)

    Harris, Craig

    2012-01-01

    The rapid expansion and evolution of epigenetics as a core scientific discipline have raised new questions about how endogenous and environmental factors can inform the mechanisms through which biological form and function are regulated. Existing and proposed animal models used for epigenetic research have targeted a myriad of health and disease endpoints that may be acute, chronic, and transgenerational in nature. Initiating events and outcomes may extend across the entire lifespan to elicit unanticipated phenotypes that are of particular concern to institutional animal care and use committees (IACUCs). The dynamics and plasticity of epigenetic mechanisms produce effects and consequences that are manifest differentially within discreet spatial and temporal contexts, including prenatal development, stem cells, assisted reproductive technologies, production of sexual dimorphisms, senescence, and others. Many dietary and nutritional interventions have also been shown to have a significant impact on biological functions and disease susceptibilities through altered epigenetic programming. The environmental, chemical, toxic, therapeutic, and psychosocial stressors used in animal studies to elicit epigenetic changes can become extreme and should raise IACUC concerns for the well-being and proper care of all research animals involved. Epigenetics research is rapidly becoming an integral part of the search for mechanisms in every major area of biomedical and behavioral research and will foster the continued development of new animal models. From the IACUC perspective, care must be taken to acknowledge the particular needs and concerns created by superimposition of epigenetic mechanisms over diverse fields of investigation to ensure the proper care and use of animals without impeding scientific progress.

  19. Epigenetic rejuvenation

    OpenAIRE

    Manukyan, Maria; Singh, Prim B

    2012-01-01

    Induced pluripotent stem (iPS) cells have provided a rational means of obtaining histo-compatible tissues for ‘patient-specific’ regenerative therapies (Hanna et al. 2010; Yamanaka & Blau 2010). Despite the obvious potential of iPS cell-based therapies, there are certain problems that must be overcome before these therapies can become safe and routine (Ohi et al. 2011; Pera 2011). As an alternative, we have recently explored the possibility of using ‘epigenetic rejuvenation’, where the specia...

  20. 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 .....

  1. Epigenetics and its implications for ecotoxicology.

    Science.gov (United States)

    Vandegehuchte, Michiel B; Janssen, Colin R

    2011-05-01

    Epigenetics is the study of mitotically or meiotically heritable changes in gene function that occur without a change in the DNA sequence. Interestingly, epigenetic changes can be triggered by environmental factors. Environmental exposure to e.g. metals, persistent organic pollutants or endocrine disrupting chemicals has been shown to modulate epigenetic marks, not only in mammalian cells or rodents, but also in environmentally relevant species such as fish or water fleas. The associated changes in gene expression often lead to modifications in the affected organism's phenotype. Epigenetic changes can in some cases be transferred to subsequent generations, even when these generations are no longer exposed to the external factor which induced the epigenetic change, as observed in a study with fungicide exposed rats. The possibility of this phenomenon in other species was demonstrated in water fleas exposed to the epigenetic drug 5-azacytidine. This way, populations can experience the effects of their ancestors' exposure to chemicals, which has implications for environmental risk assessment. More basic research is needed to assess the potential phenotypic and population-level effects of epigenetic modifications in different species and to evaluate the persistence of chemical exposure-induced epigenetic effects in multiple subsequent generations.

  2. Rapid Molecular Profiling of Myeloproliferative Neoplasms Using Targeted Exon Resequencing of 86 Genes Involved in JAK-STAT Signaling and Epigenetic Regulation.

    Science.gov (United States)

    Magor, Graham W; Tallack, Michael R; Klose, Nathan M; Taylor, Debra; Korbie, Darren; Mollee, Peter; Trau, Matt; Perkins, Andrew C

    2016-09-01

    Myeloproliferative neoplasms (MPNs) are a heterogeneous group of blood disorders characterized by excess production of mature blood cells and an increased risk of late transformation to acute myeloid leukemia or primary myelofibrosis. Approximately 15% of MPN cases do not carry mutations in JAK2, CALR, or MPL and are thus often referred to as triple-negative cases. These are caused by a diverse set of rare mutations in cytokine receptors, JAK-STAT signaling pathway components, or epigenetic modifiers. In addition, some cases diagnosed as MPN are reactive rather than clonal disorders, so a negative result from a genetic screen can be informative. To obtain a comprehensive rapid molecular diagnosis for most MPNs, we developed an assay to detect genetic mutations (single nucleotide variants and/or small insertions/deletions) in 86 genes using targeted exon resequencing (AmpliSeq) and a bench-top semiconductor machine (Ion Torrent Personal Genome Machine). Our assay reliably detects well characterized mutations in JAK2, CALR, and MPL, but also rarer mutations in ASXL1, TET2, SH2B3, and other genes. Some of these mutations are novel. We find multiple mutations in advanced cases, suggesting co-operation between Janus kinase-STAT pathway mutations and epigenetic mutations in disease progression. This assay can be used to follow molecular progression, clonal heterogeneity, and drug resistance in MPNs. PMID:27449473

  3. 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.

  4. 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 ...

  5. Epigenetic drugs that do not target enzyme activity.

    Science.gov (United States)

    Owen, Dafydd R; Trzupek, John D

    2014-06-01

    While the installation and removal of epigenetic post-translational modifications or ‘marks’ on both DNA and histone proteins are the tangible outcome of enzymatically catalyzed processes, the role of the epigenetic reader proteins looks, at first, less obvious. As they do not catalyze a chemical transformation or process as such, their role is not enzymatic. However, this does not preclude them from being potential targets for drug discovery as their function is clearly correlated to transcriptional activity and as a class of proteins, they appear to have binding sites of sufficient definition and size to be inhibited by small molecules. This suggests that this third class of epigenetic proteins that are involved in the interpretation of post-translational marks (as opposed to the creation or deletion of marks) may represent attractive targets for drug discovery efforts. This review mainly summarizes selected publications, patent literature and company disclosures on these non-enzymatic epigenetic reader proteins from 2009 to the present.

  6. 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...

  7. 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.

  8. Epigenetic regulation in Parkinson's disease.

    Science.gov (United States)

    Labbé, Catherine; Lorenzo-Betancor, Oswaldo; Ross, Owen A

    2016-10-01

    Recent efforts have shed new light on the epigenetic mechanisms driving gene expression alterations associated with Parkinson's disease (PD) pathogenesis. Changes in gene expression are a well-established cause of PD, and epigenetic mechanisms likely play a pivotal role in regulation. Studies in families with PD harboring duplications and triplications of the SNCA gene have demonstrated that gene dosage is associated with increased expression of both SNCA mRNA and protein, and correlates with a fulminant disease course. Furthermore, it is postulated that even subtle changes in SNCA expression caused by common variation is associated with disease risk. Of note, genome-wide association studies have identified over 30 loci associated with PD with most signals located in non-coding regions of the genome, thus likely influencing transcript expression levels. In health, epigenetic mechanisms tightly regulate gene expression, turning genes on and off to balance homeostasis and this, in part, explains why two cells with the same DNA sequence will have different RNA expression profiles. Understanding this phenomenon will be crucial to our interpretation of the selective vulnerability observed in neurodegeneration and specifically dopaminergic neurons in the PD brain. In this review, we discuss epigenetic mechanisms, such as DNA methylation and histone modifications, involved in regulating the expression of genes relevant to PD, RNA-based mechanisms, as well as the effect of toxins and potential epigenetic-based treatments for PD.

  9. 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.

  10. Review of Maritime Accidents Involving Chemicals – Special Focus on the Baltic Sea

    Directory of Open Access Journals (Sweden)

    J.M. Häkkinen

    2014-06-01

    Full Text Available Transport and handling of hazardous chemicals and chemical products around the world’s waters and ports have considerably increased over the last 20 years. Thus, the risk of major pollution accidents has also increased. Past incidents/accidents are, when reported in detail, first hand sources of information on what may happen again. This paper provides an overview of the past tanker accidents in the Baltic Sea and chemical related accidents in seas worldwide. The aim is to find out what can be learned from past accidents, especially from the environmental point of view. The study is carried out as a literature review and as a statistical review. The study revealed that the risk of a chemical accident is highest in seas where the highest tonnes of chemicals are transported, the density of maritime traffic is highest and, of course, in the ship-shore interface where unloading/loading takes place. Incidents involving chemical spills are statistically much less likely to occur than oil spills. However, chemical cargoes can be more dangerous to humans and property because chemicals can be more combustible, poisonous, irritating and reactive. The most important difference between a chemical and an oil spill may be related to response actions. In case of a chemical accident, the air quality or the risk of explosion should be more carefully evaluated before any response actions are taken. In case of chemical spills, the response is more limited in comparison to oil. Actually, very little is known about the actual marine pollution effect of most of highly transported substances. From the environmental point of view, the previous studies have highlighted accidents in which pesticides were released to water, but also substances considered as non-pollutants (vegetable oils seem to have a negative effect on biota in the water environment.

  11. 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

  12. Peromyscus as a Mammalian Epigenetic Model

    Directory of Open Access Journals (Sweden)

    Kimberly R. Shorter

    2012-01-01

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

  13. Epigenetics, 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.

  14. Epigenetic drift, epigenetic clocks and cancer risk.

    Science.gov (United States)

    Zheng, Shijie C; Widschwendter, Martin; Teschendorff, Andrew E

    2016-05-01

    It is well-established that the DNA methylation landscape of normal cells undergoes a gradual modification with age, termed as 'epigenetic drift'. Here, we review the current state of knowledge of epigenetic drift and its potential role in cancer etiology. We propose a new terminology to help distinguish the different components of epigenetic drift, with the aim of clarifying the role of the epigenetic clock, mitotic clocks and active changes, which accumulate in response to environmental disease risk factors. We further highlight the growing evidence that epigenetic changes associated with cancer risk factors may play an important causal role in cancer development, and that monitoring these molecular changes in normal cells may offer novel risk prediction and disease prevention strategies.

  15. Epigenetic drift, epigenetic clocks and cancer risk.

    Science.gov (United States)

    Zheng, Shijie C; Widschwendter, Martin; Teschendorff, Andrew E

    2016-05-01

    It is well-established that the DNA methylation landscape of normal cells undergoes a gradual modification with age, termed as 'epigenetic drift'. Here, we review the current state of knowledge of epigenetic drift and its potential role in cancer etiology. We propose a new terminology to help distinguish the different components of epigenetic drift, with the aim of clarifying the role of the epigenetic clock, mitotic clocks and active changes, which accumulate in response to environmental disease risk factors. We further highlight the growing evidence that epigenetic changes associated with cancer risk factors may play an important causal role in cancer development, and that monitoring these molecular changes in normal cells may offer novel risk prediction and disease prevention strategies. PMID:27104983

  16. 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.

  17. 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. PMID:27445807

  18. 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. PMID:27445807

  19. Epigenetic inheritance and plasticity: The responsive germline.

    Science.gov (United States)

    Jablonka, Eva

    2013-04-01

    Developmental plasticity, the capacity of a single genotype to give rise to different phenotypes, affects evolutionary dynamics by influencing the rate and direction of phenotypic change. It is based on regulatory changes in gene expression and gene products, which are partially controlled by epigenetic mechanisms. Plasticity involves not just epigenetic changes in somatic cells and tissues; it can also involve changes in germline cells. Germline epigenetic plasticity increases evolvability, the capacity to generate heritable, selectable, phenotypic variations, including variations that lead to novel functions. I discuss studies that show that some complex adaptive responses to new challenges are mediated by germline epigenetic processes, which can be transmitted over variable number of generations, and argue that the heritable variations that are generated epigenetically have an impact on both small-scale and large-scale aspects of evolution. First, I review some recent ecological studies and models that show that germline (gametic) epigenetic inheritance can lead to cumulative micro-evolutionary changes that are rapid and semi-directional. I suggest that "priming" and "epigenetic learning" may be of special importance in generating heritable, fine-tuned adaptive responses in populations. Second, I consider work showing how genomic and environmental stresses can also lead to epigenome repatterning, and produce changes that are saltational.

  20. Understanding neurological disease mechanisms in the era of epigenetics.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2013-06-01

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

  1. 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...

  2. 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.

  3. 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

  4. Targeting cancer epigenetics: Linking basic biology to clinical medicine.

    Science.gov (United States)

    Shinjo, Keiko; Kondo, Yutaka

    2015-12-01

    Recent studies provide compelling evidence that epigenetic dysregulation is involved in almost every step of tumor development and progression. Differences in tumor behavior, which ultimately reflects clinical outcome, can be explained by variations in gene expression patterns generated by epigenetic mechanisms, such as DNA methylation. Therefore, epigenetic abnormalities are considered potential biomarkers and therapeutic targets. DNA methylation is stable at certain specific loci in cancer cells and predominantly reflects the characteristic clinicopathological features. Thus, it is an ideal biomarker for cancer screening, classification and prognostic purposes. Epigenetic treatment for cancers is based on the pharmacologic targeting of various core transcriptional programs that sustains cancer cell identity. Therefore, targeting aberrant epigenetic modifiers may be effective for multiple processes compared with using a selective inhibitor of aberrant single signaling pathway. This review provides an overview of the epigenetic alterations in human cancers and discusses about novel therapeutic strategies targeting epigenetic alterations.

  5. Epigenetic modifications as regulatory elements of autophagy in cancer.

    Science.gov (United States)

    Sui, Xinbing; Zhu, Jing; Zhou, Jichun; Wang, Xian; Li, Da; Han, Weidong; Fang, Yong; Pan, Hongming

    2015-05-01

    Epigenetic modifications have been considered as hallmarks of cancer and play an important role in tumor initiation and development. Epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs, may regulate cell cycle and apoptosis, as well as macroautophagy (hereafter referred to as autophagy). Autophagy, as a crucial cellular homeostatic mechanism, performs a dual role, having pro-survival or pro-death properties. A variety of signaling pathways including epigenetic control have been implicated in the upregulation or downregulation of autophagy. However, the role of epigenetic regulation in autophagy is still less well acknowledged. Recent studies have linked epigenetic control to the autophagic process. Some epigenetic modifiers are also involved in the regulation of autophagy and potentiate the efficacy of traditional therapeutics. Thus, understanding the novel functions of epigenetic control in autophagy may allow us to develop potential therapeutic approaches for cancer treatment.

  6. Development, epigenetics and metabolic programming

    Science.gov (United States)

    Godfrey, Keith M; Costello, Paula; Lillycrop, Karen

    2016-01-01

    It is now widely recognised that the environment in early life can have important effects on human growth and development, including the “programming” of far reaching effects on the risk of developing common metabolic and other non-communicable diseases in later life. We have shown that greater childhood adiposity is associated with higher maternal adiposity, low maternal vitamin D status, excessive gestational weight gain, and short duration of breastfeeding; maternal dietary patterns in pregnancy and vitamin D status have been linked with childhood bone mineral content and muscle function. Human studies have identified fetal liver blood flow adaptations and epigenetic changes as potential mechanisms that could link maternal influences with offspring body composition. In experimental studies there is now substantial evidence that the environment during early life induces altered phenotypes through epigenetic mechanisms. Epigenetic processes such as DNA methylation, covalent modifications of histones and non-coding RNAs can induce changes in gene expression without a change in DNA base sequence. Such processes are involved in cell differentiation and genomic imprinting, as well as the phenomenon of developmental plasticity in response to environmental influences. Elucidation of such epigenetic processes may enable early intervention strategies to improve early development and growth. PMID:27088334

  7. Epigenetics and Peripheral Artery Disease.

    Science.gov (United States)

    Golledge, Jonathan; Biros, Erik; Bingley, John; Iyer, Vikram; Krishna, Smriti M

    2016-04-01

    The term epigenetics is usually used to describe inheritable changes in gene function which do not involve changes in the DNA sequence. These typically include non-coding RNAs, DNA methylation and histone modifications. Smoking and older age are recognised risk factors for peripheral artery diseases, such as occlusive lower limb artery disease and abdominal aortic aneurysm, and have been implicated in promoting epigenetic changes. This brief review describes studies that have associated epigenetic factors with peripheral artery diseases and investigations which have examined the effect of epigenetic modifications on the outcome of peripheral artery diseases in mouse models. Investigations have largely focused on microRNAs and have identified a number of circulating microRNAs associated with human peripheral artery diseases. Upregulating or antagonising a number of microRNAs has also been reported to limit aortic aneurysm development and hind limb ischemia in mouse models. The importance of DNA methylation and histone modifications in peripheral artery disease has been relatively little studied. Whether circulating microRNAs can be used to assist identification of patients with peripheral artery diseases and be modified in order to improve the outcome of peripheral artery disease will require further investigation.

  8. Alcohol Metabolism and Epigenetics Changes

    Science.gov (United States)

    Zakhari, Samir

    2013-01-01

    Metabolites, including those generated during ethanol metabolism, can impact disease states by binding to transcription factors and/or modifying chromatin structure, thereby altering gene expression patterns. For example, the activities of enzymes involved in epigenetic modifications such as DNA and histone methylation and histone acetylation, are influenced by the levels of metabolites such as nicotinamide adenine dinucleotide (NAD), adenosine triphosphate (ATP), and S-adenosylmethionine (SAM). Chronic alcohol consumption leads to significant reductions in SAM levels, thereby contributing to DNA hypomethylation. Similarly, ethanol metabolism alters the ratio of NAD+ to reduced NAD (NADH) and promotes the formation of reactive oxygen species and acetate, all of which impact epigenetic regulatory mechanisms. In addition to altered carbohydrate metabolism, induction of cell death, and changes in mitochondrial permeability transition, these metabolism-related changes can lead to modulation of epigenetic regulation of gene expression. Understanding the nature of these epigenetic changes will help researchers design novel medications to treat or at least ameliorate alcohol-induced organ damage. PMID:24313160

  9. 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

  10. Epigenetic control of GnRH neurons

    Directory of Open Access Journals (Sweden)

    Joseph Raymond Kurian

    2013-05-01

    Full Text Available Epigenetic modifications to the genome, including DNA methylation and histone modifications, occur in response to external stimuli. Reproductive function is highly sensitive to environmental conditions including season, diet, hormonal changes, and exposure to chemical contaminants. GnRH neurons, which play a key role in reproduction, are particularly sensitive to various environmental stimuli. We recently reported that the rhesus monkey GnRH gene exhibits distinct epigenetic differentiation during embryonic development. More recently, we further found that a similar epigenetic phenomenon occurs across puberty. In this article, we highlight recent findings, suggest implications of these findings (or potential mechanisms and then discuss current challenges as well as future work. Consequently, this review will provide background to understand the epigenetic control of GnRH neurons as a link between the environment and reproductive function.

  11. 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,...

  12. 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 ...

  13. Epigenetics and Cellular Metabolism

    Science.gov (United States)

    Xu, Wenyi; Wang, Fengzhong; Yu, Zhongsheng; Xin, Fengjiao

    2016-01-01

    Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well. PMID:27695375

  14. Epigenetics and Cellular Metabolism

    Science.gov (United States)

    Xu, Wenyi; Wang, Fengzhong; Yu, Zhongsheng; Xin, Fengjiao

    2016-01-01

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

  15. Epigenetics 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...

  16. 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

  17. 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...

  18. Multi-objective decisions in land-use planning involving chemical sites

    DEFF Research Database (Denmark)

    Rasmussen, B.; Bertelsen, I.; Burchard, V.;

    1999-01-01

    A methodology for land-use planning involving chemical sites has been developed for making decisions in local and regional administrations. The methodology structures the planning process in seven steps, where one can loop through the steps several times.Essential parts of the methodology...... case studies from Sweden and Denmark have been used, and essential topics and results from two Danishcase studies are presented. The work described in this report is financially supported by the CEC Environment and Climate Programme (contract no. ENV4-CT96-0241)....

  19. 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 ...

  20. 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...

  1. Miscible viscous fingering involving viscosity changes of the displacing fluid by chemical reactions

    Science.gov (United States)

    Nagatsu, Yuichiro; Iguchi, Chika; Matsuda, Kenji; Kato, Yoshihito; Tada, Yutaka

    2010-02-01

    In our previous study, we experimentally studied the effects of changes in the viscosity of the displaced more-viscous liquid by instantaneous reactions on miscible viscous fingering pattern [Y. Nagatsu, K. Matsuda, Y. Kato, and Y. Tada, "Experimental study on miscible viscous fingering involving viscosity changes induced by variations in chemical species concentrations due to chemical reactions," J. Fluid Mech. 571, 475 (2007)]. In the present study, experiments have been performed on the miscible viscous fingering involving changes in the viscosity of the displacing less-viscous liquid by instantaneous reactions in a radial Hele-Shaw cell. We have found that the shielding effect is suppressed and the fingers are widened when the viscosity is increased. As a result, the reaction makes the fingering pattern denser. In contrast, the shielding effect is enhanced, and the fingers are narrowed when the viscosity is decreased. As a result, the reaction makes the fingering pattern less dense. These results are essentially same as those obtained by the above-mentioned previous study. This shows that the effects of changes in the viscosity due to the instantaneous reactions are independent of whether the changes occur in the displaced liquid or in the displacing liquid. A mechanism for the independence is discussed.

  2. 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

  3. 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

  4. 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...

  5. 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

  6. Epigenetic mechanisms in gastric cancer.

    Science.gov (United States)

    Gigek, Carolina Oliveira; Chen, Elizabeth Suchi; Calcagno, Danielle Queiroz; Wisnieski, Fernanda; Burbano, Rommel Rodriguez; Smith, Marilia Arruda Cardoso

    2012-06-01

    Cancer is considered one of the major health issues worldwide, and gastric cancer accounted for 8% of total cases and 10% of total deaths in 2008. Gastric cancer is considered an age-related disease, and the total number of newly diagnosed cases has been increasing as a result of the higher life expectancy. Therefore, the basic mechanisms underlying gastric tumorigenesis is worth investigation. This review provides an overview of the epigenetic mechanisms, such as DNA methylation, histone modifications, chromatin remodeling complex and miRNA, involved in gastric cancer. As the studies in gastric cancer continue, the mapping of an epigenome code is not far for this disease. In conclusion, an epigenetic therapy might appear in the not too distant future.

  7. 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.

  8. Epigenetics and cancer

    DEFF Research Database (Denmark)

    Lund, Anders H; van Lohuizen, Maarten

    2004-01-01

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

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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 ...

  15. 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.

  16. 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

  17. 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...

  18. 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

  19. Epigenetic changes in diabetes.

    Science.gov (United States)

    Al-Haddad, Rami; Karnib, Nabil; Assaad, Rawad Abi; Bilen, Yara; Emmanuel, Nancy; Ghanem, Anthony; Younes, Joe; Zibara, Victor; Stephan, Joseph S; Sleiman, Sama F

    2016-06-20

    The incidence of diabetes is increasing worldwide. Diabetes is quickly becoming one of the leading causes of death. Diabetes is a genetic disease; however, the environment plays critical roles in its development and progression. Epigenetic changes often translate environmental stimuli to changes in gene expression. Changes in epigenetic marks and differential regulation of epigenetic modulators have been observed in different models of diabetes and its associated complications. In this minireview, we will focus DNA methylation, Histone acetylation and methylation and their roles in the pathogenesis of diabetes. PMID:27130819

  20. 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…

  1. 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...

  2. [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

  3. 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

  4. 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.

  5. Epigenetics in Rheumatoid Arthritis

    OpenAIRE

    Trenkmann, M.; Brock, M; Ospelt, C; Gay, S.

    2010-01-01

    Epigenetics is a steadily growing research area. In many human diseases, especially in cancers, but also in autoimmune diseases, epigenetic aberrations have been found. Rheumatoid arthritis is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints. Even though the etiology is not yet fully understood, rheumatoid arthritis is generally considered to be caused by a combination of genetic predisposition, deregulated immunomodulation, and environmental infl...

  6. Epigenetic Regulation of B Lymphocyte Differentiation, Transdifferentiation, and Reprogramming

    Directory of Open Access Journals (Sweden)

    Bruna Barneda-Zahonero

    2012-01-01

    Full Text Available B cell development is a multistep process that is tightly regulated at the transcriptional level. In recent years, investigators have shed light on the transcription factor networks involved in all the differentiation steps comprising B lymphopoiesis. The interplay between transcription factors and the epigenetic machinery involved in establishing the correct genomic landscape characteristic of each cellular state is beginning to be dissected. The participation of “epigenetic regulator-transcription factor” complexes is also crucial for directing cells during reprogramming into pluripotency or lineage conversion. In this context, greater knowledge of epigenetic regulation during B cell development, transdifferentiation, and reprogramming will enable us to understand better how epigenetics can control cell lineage commitment and identity. Herein, we review the current knowledge about the epigenetic events that contribute to B cell development and reprogramming.

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. Epigenetics and the evolution of Darwin's Finches.

    Science.gov (United States)

    Skinner, Michael K; Gurerrero-Bosagna, Carlos; Haque, M Muksitul; Nilsson, Eric E; Koop, Jennifer A H; Knutie, Sarah A; Clayton, Dale H

    2014-07-24

    The prevailing theory for the molecular basis of evolution involves genetic mutations that ultimately generate the heritable phenotypic variation on which natural selection acts. However, epigenetic transgenerational inheritance of phenotypic variation may also play an important role in evolutionary change. A growing number of studies have demonstrated the presence of epigenetic inheritance in a variety of different organisms that can persist for hundreds of generations. The possibility that epigenetic changes can accumulate over longer periods of evolutionary time has seldom been tested empirically. This study was designed to compare epigenetic changes among several closely related species of Darwin's finches, a well-known example of adaptive radiation. Erythrocyte DNA was obtained from five species of sympatric Darwin's finches that vary in phylogenetic relatedness. Genome-wide alterations in genetic mutations using copy number variation (CNV) were compared with epigenetic alterations associated with differential DNA methylation regions (epimutations). Epimutations were more common than genetic CNV mutations among the five species; furthermore, the number of epimutations increased monotonically with phylogenetic distance. Interestingly, the number of genetic CNV mutations did not consistently increase with phylogenetic distance. The number, chromosomal locations, regional clustering, and lack of overlap of epimutations and genetic mutations suggest that epigenetic changes are distinct and that they correlate with the evolutionary history of Darwin's finches. The potential functional significance of the epimutations was explored by comparing their locations on the genome to the location of evolutionarily important genes and cellular pathways in birds. Specific epimutations were associated with genes related to the bone morphogenic protein, toll receptor, and melanogenesis signaling pathways. Species-specific epimutations were significantly overrepresented in these

  13. 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...

  14. Epigenetic learning in non-neural organisms.

    Science.gov (United States)

    Ginsburg, Simona; Jablonka, Eva

    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.

  15. 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.

  16. Epigenetic aberrations and therapeutic implications in gliomas.

    Science.gov (United States)

    Natsume, Atsushi; Kondo, Yutaka; Ito, Motokazu; Motomura, Kazuya; Wakabayashi, Toshihiko; Yoshida, Jun

    2010-06-01

    Almost all cancer cells have multiple epigenetic abnormalities, which combine with genetic changes to affect many cellular processes, including cell proliferation and invasion, by silencing tumor-suppressor genes. In this review, we focus on the epigenetic mechanisms of DNA hypomethylation and CpG island hypermethylation in gliomas. Aberrant hypermethylation in promoter CpG islands has been recognized as a key mechanism involved in the silencing of cancer-associated genes and occurs at genes with diverse functions related to tumorigenesis and tumor progression. Such promoter hypermethylation can modulate the sensitivity of glioblastomas to drugs and radiotherapy. As an example, the methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter is a specific predictive biomarker of tumor responsiveness to chemotherapy with alkylating agents. Further, we reviewed reports on pyrosequencing - a simple technique for the accurate and quantitative analysis of DNA methylation. We believe that the quantification of MGMT methylation by pyrosequencing might enable the selection of patients who are most likely to benefit from chemotherapy. Finally, we also evaluated the potential of de novo NY-ESO-1, the most immunogenic cancer/testis antigen (CTA) discovered thus far, as an immunotherapy target. The use of potent epigenetics-based therapy for cancer cells might restore the abnormally regulated epigenomes to a more normal state through epigenetic reprogramming. Thus, epigenetic therapy may be a promising and potent treatment for human neoplasia.

  17. 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.

  18. 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

  19. 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

  20. Genetic and epigenetic basis of psoriasis pathogenesis.

    Science.gov (United States)

    Chandra, Aditi; Ray, Aditi; Senapati, Swapan; Chatterjee, Raghunath

    2015-04-01

    Psoriasis is a chronic inflammatory skin disease whose prevalence varies among different populations worldwide. It is a complex multi-factorial disease and the exact etiology is largely unknown. Family based studies have indicated a genetic predisposition; however they cannot fully explain the disease pathogenesis. In addition to genetic susceptibility, environmental as well as gender and age related factors were also been found to be associated. Recently, imbalances in epigenetic networks are indicated to be causative elements in psoriasis. The present knowledge of epigenetic involvement, mainly the DNA methylation, chromatin modifications and miRNA deregulation is surveyed here. An integrated approach considering genetic and epigenetic anomalies in the light of immunological network may explore the pathogenesis of psoriasis.

  1. 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...

  2. 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

  3. Epigenetics and epilepsy.

    Science.gov (United States)

    Roopra, Avtar; Dingledine, Raymond; Hsieh, Jenny

    2012-12-01

    Seizures can give rise to enduring changes that reflect alterations in gene-expression patterns, intracellular and intercellular signaling, and ultimately network alterations that are a hallmark of epilepsy. A growing body of literature suggests that long-term changes in gene transcription associated with epilepsy are mediated via modulation of chromatin structure. One transcription factor in particular, repressor element 1-silencing transcription factor (REST), has received a lot of attention due to the possibility that it may control fundamental transcription patterns that drive circuit excitability, seizures, and epilepsy. REST represses a suite of genes in the nervous system by utilizing nuclear protein complexes that were originally identified as mediators of epigenetic inheritance. Epigenetics has traditionally referred to mechanisms that allow a heritable change in gene expression in the absence of DNA mutation. However a more contemporaneous definition acknowledges that many of the mechanisms used to perpetuate epigenetic traits in dividing cells are utilized by neurons to control activity-dependent gene expression. This review surveys what is currently understood about the role of epigenetic mechanisms in epilepsy. We discuss how REST controls gene expression to affect circuit excitability and neurogenesis in epilepsy. We also discuss how the repressor methyl-CpG-binding protein 2 (MeCP2) and activator cyclic AMP response element binding protein (CREB) regulate neuronal activity and are themselves controlled by activity. Finally we highlight possible future directions in the field of epigenetics and epilepsy.

  4. 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.

  5. 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.

  6. Prospects for the development of epigenetic drugs for CNS conditions.

    Science.gov (United States)

    Szyf, Moshe

    2015-07-01

    Advances in our understanding of the epigenetic mechanisms that control gene expression in the central nervous system (CNS) and their role in neuropsychiatric disorders are paving the way for a potential new therapeutic approach that is focused on reversing the epigenetic underpinnings of neuropsychiatric conditions. In this article, the complexity of epigenetic processes and the current level of proof for their involvement in CNS disorders are discussed. The preclinical evidence for efficacy of pharmacological approaches that target epigenetics in the CNS and the particular challenges of this approach are also examined. Finally, strategies to address these challenges through the development of improved evidence-based epigenetic therapeutics and through combining pharmacological and behavioural approaches are presented.

  7. Transgenerational epigenetic inheritance: adaptation through the germline epigenome?

    Science.gov (United States)

    Prokopuk, Lexie; Western, Patrick S; Stringer, Jessica M

    2015-08-01

    Epigenetic modifications direct the way DNA is packaged into the nucleus, making genes more or less accessible to transcriptional machinery and influencing genomic stability. Environmental factors have the potential to alter the epigenome, allowing genes that are silenced to be activated and vice versa. This ultimately influences disease susceptibility and health in an individual. Furthermore, altered chromatin states can be transmitted to subsequent generations, thus epigenetic modifications may provide evolutionary mechanisms that impact on adaptation to changed environments. However, the mechanisms involved in establishing and maintaining these epigenetic modifications during development remain unclear. This review discusses current evidence for transgenerational epigenetic inheritance, confounding issues associated with its study, and the biological relevance of altered epigenetic states for subsequent generations.

  8. 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.

  9. 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.

  10. Epigenetics and lifestyle

    Science.gov (United States)

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

    2013-01-01

    The concept of “lifestyle” includes different factors such as nutrition, behavior, stress, physical activity, working habits, smoking and alcohol consumption. Increasing evidence shows that environmental and lifestyle factors may influence epigenetic mechanisms, such as DNA methylation, histone acetylation and microRNA expression. Several lifestyle factors have been identified that might modify epigenetic patterns, such as diet, obesity, physical activity, tobacco smoking, alcohol consumption, environmental pollutants, psychological stress, and working on night shifts. Most studies conducted so far have been centered on DNA methylation, whereas only a few investigations have studied lifestyle factors in relation to histone modifications and miRNAs. Here, we review current evidence indicating that lifestyle factors might affect human health via epigenetic mechanisms. PMID:22122337

  11. 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

  12. 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.

  13. Epigenetic Therapy in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Stephen V Liu

    2013-05-01

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

  14. Epigenetics in plant tissue culture

    NARCIS (Netherlands)

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

    2011-01-01

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

  15. 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.

  16. 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

  17. Plant Epigenetics: From genomes to epigenomes

    Directory of Open Access Journals (Sweden)

    Alain RIVAL

    2010-09-01

    Full Text Available Epigenetics is the study of heritable changes in gene expression that occur without a change in the DNA sequence. In recent years, this field has attracted increasing attention as more epigenetic mechanisms affecting gene activity are being discovered. Such processes involve a complex interplay between DNA methylation, histone modifications, and non-coding RNAs, notably small interfering RNAs (siRNAs and micro RNAs (miRNAs. Epigenetic regulation is not only important for generating differentiated cell types during plant development, but also in maintaining the stability and integrity of their respective gene expression profiles. Although epigenetic processes are essential for normal development, they can become misdirected which leads to abnormal phenotypes and diseases, especially cancer. Sensing environmental changes and initiating a quick, reversible and appropriate response in terms of modified gene expression is of paramount importance for plants which are sessile autotrophs. Although epigenetic mechanisms help to protect plant cells from the activity of parasitic sequences such as transposable elements, this defense can complicate the genetic engineering process through transcriptional gene silencing. Epigenetic phenomena have economic relevance in the case of somaclonal variation: a genetic and phenotypic variation among clonally propagated plants from a single donor genotype. The success of sequencing projects on model plants has created widespread interest in exploring the epigenome in order to elucidate how plant cell decipher and execute the information stored and encoded in the genome. New high-throughput techniques are making it easier to map DNA methylation patterns on a large scale and results have already provided surprises.

  18. 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...

  19. 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

  20. Epigenetics, Darwin, and Lamarck

    Science.gov (United States)

    Penny, David

    2015-01-01

    It is not really helpful to consider modern environmental epigenetics as neo-Lamarckian; and there is no evidence that Lamarck considered the idea original to himself. We must all keep learning about inheritance, but attributing modern ideas to early researchers is not helpful, and can be misleading. PMID:26026157

  1. Epigenetic Therapy for Breast Cancer

    Directory of Open Access Journals (Sweden)

    Xiao-Yan Zhong

    2011-07-01

    Full Text Available 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 Administration as anti-cancer drugs. Therefore, the uses of epigenetic targets are believed to have great potential as a lasting favorable approach in treating breast cancer.

  2. Nest marking behavior and chemical composition of olfactory cues involved in nest recognition in Megachile rotundata.

    Science.gov (United States)

    Guédot, Christelle; Buckner, James S; Hagen, Marcia M; Bosch, Jordi; Kemp, William P; Pitts-Singer, Theresa L

    2013-08-01

    In-nest observations of the solitary bee, Megachile rotundata (F.), revealed that nesting females apply olfactory cues to nests for nest recognition. On their way in and out of the nest, females drag the abdomen along the entire length of the nest, and sometimes deposit fluid droplets from the tip of the abdomen. The removal of bee-marked sections of the nest resulted in hesitation and searching behavior by females, indicating the loss of olfactory cues used for nest recognition. Chemical analysis of female cuticles and the deposits inside marked nesting tubes revealed the presence of hydrocarbons, wax esters, fatty aldehydes, and fatty alcohol acetate esters. Chemical compositions were similar across tube samples, but proportionally different from cuticular extracts. These findings reveal the importance of lipids as chemical signals for nest recognition and suggest that the nest-marking cues are derived from a source in addition to, or other than, the female cuticle. PMID:23905742

  3. 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

  4. 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

  5. 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

  6. 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...

  7. 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.

  8. Epigenetic regulation of cystatins in cancer.

    Science.gov (United States)

    Rivenbark, Ashley G; Coleman, William B

    2009-01-01

    Cystatins function as cysteine protease inhibitors, are expressed in numerous cell types, and regulate a number of physiological processes. Four cystatins have been extensively studied: cystatin A, cystatin B, cystatin C, and cystatin M. Aberrant regulation of cystatins occurs in a number of diseases, including cancer and certain neurodegenerative disorders. Recent advances in the understanding of cystatin function suggest that these proteins may regulate promotion or suppression of tumor growth, invasion, and metastasis. Cancer is a disease of abnormal gene expression and cancer cells exhibit aberrant epigenetic events (such as DNA methylation), leading to gene silencing. Cystatins are epigenetically silenced through DNA methylation-dependent mechanisms in several forms of cancer, including breast, pancreatic, brain, and lung. These findings suggest that DNA methylation-dependent epigenetic mechanisms may play an important role in the loss of cystatin gene expression and protein function during neoplastic transformation and/or tumor progression. This review summarizes the biological processes in which cystatins function, focuses on the neoplastic events that involve aberrant regulation of cystatins, and discusses the possible epigenetic regulation of cystatins in cancer.

  9. [Research progress of epigenetic drug decitabine in AML].

    Science.gov (United States)

    Zhang, Rui; Li, Hui-Min

    2014-10-01

    Epigenetics is a gene regulation mechanism that can be reversible and heritable, but do not involve the DNA sequence changes. DNA methylation is one of the most important epigenetic modifications, which is closely correlate with tumorigenesis. Decitabine is a methylation inhibitor, which has different action mechanism and targeting characteristics from the traditional chemotherapy, representing a new therapeutic strategy. This review mainly focuses on the anti-leukemia mechanism of decitabine and its clinical efficacy for AML.

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. Legal considerations involving chemical control of iron and other deficiencies in plants

    Energy Technology Data Exchange (ETDEWEB)

    Wallace, A; Samman, Y. S.

    1981-01-01

    Four cases of lawsuits involving use of chelating agents in plant nutrition are discussed. Three of them involved use of iron. One concerned addition of FeDTPA to nursery trees in containers. One case involved foliar application of FeHEDTA to potatoes in July by airplane. Another case not involving iron chelate was with ZnEDTA and MnEDTA with Fe as FeSO/sub 4/ later as a foliar spray. The Zn and MnEDTA were applied as a band 8 inches (20 cm) on both sides of nursery tree rows just as the buds that had been placed in the fall began growing in the spring. In the fourth case, many tomato transplants died when the transplanting was done with about 120 ml per plant of transplant solution containing besides N, P and K, about 19 mg Zn as ZnEDTA, 14 mg Mn as MnEDTA and 7 mg Fe as FeHEDTA. Cases such as these will probably discourage use of chelating agents in plant nutrition even if the chelating agents were not the damaging agent. Not enough developmental work was done on the potential toxicities from metal chelates. This trend to lawsuits makes it even more important to solve iron chlorosis problems via plant breeding.

  16. Epigenetic mechanisms underlying learning and the inheritance of learned behaviors.

    Science.gov (United States)

    Dias, Brian G; Maddox, Stephanie A; Klengel, Torsten; Ressler, Kerry J

    2015-02-01

    Gene expression and regulation is an important sculptor of the behavior of organisms. Epigenetic mechanisms regulate gene expression not by altering the genetic alphabet but rather by the addition of chemical modifications to proteins associated with the alphabet or of methyl marks to the alphabet itself. Being dynamic, epigenetic mechanisms of gene regulation serve as an important bridge between environmental stimuli and genotype. In this review, we outline epigenetic mechanisms by which gene expression is regulated in animals and humans. Using fear learning as a framework, we then delineate how such mechanisms underlie learning and stress responsiveness. Finally, we discuss how epigenetic mechanisms might inform us about the transgenerational inheritance of behavioral traits that are being increasingly reported.

  17. Epigenetic mechanisms underlying the pathogenesis of neurogenetic diseases.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2014-10-01

    There have been considerable advances in uncovering the complex genetic mechanisms that underlie nervous system disease pathogenesis, particularly with the advent of exome and whole genome sequencing techniques. The emerging field of epigenetics is also providing further insights into these mechanisms. Here, we discuss our understanding of the interplay that exists between genetic and epigenetic mechanisms in these disorders, highlighting the nascent field of epigenetic epidemiology-which focuses on analyzing relationships between the epigenome and environmental exposures, development and aging, other health-related phenotypes, and disease states-and next-generation research tools (i.e., those leveraging synthetic and chemical biology and optogenetics) for examining precisely how epigenetic modifications at specific genomic sites affect disease processes.

  18. Epigenetic memory in kidney diseases.

    Science.gov (United States)

    Mimura, Imari

    2016-02-01

    Epigenetic mechanisms have been the focus of intensive research. De Marinis et al. demonstrated that high glucose levels exert stimulatory effects on activation histone marks, leading to the upregulation of thioredoxin-interacting protein (TXNIP) gene expression, which is proinflammatory. They also showed that the effect was reversed by the inhibition of histone acetyltransferase, suggesting a new therapeutic approach for improving diabetic kidney disease. Epigenetic changes are memorized as epigenetic memory that could exacerbate diabetic complications.

  19. The complexity of epigenetic diseases.

    Science.gov (United States)

    Brazel, Ailbhe Jane; Vernimmen, Douglas

    2016-01-01

    Over the past 30 years, a plethora of pathogenic mutations affecting enhancer regions and epigenetic regulators have been identified. Coupled with more recent genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) implicating major roles for regulatory mutations in disease, it is clear that epigenetic mechanisms represent important biomarkers for disease development and perhaps even therapeutic targets. Here, we discuss the diversity of disease-causing mutations in enhancers and epigenetic regulators, with a particular focus on cancer.

  20. 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).

  1. Cancer type-specific epigenetic changes: gastric cancer.

    Science.gov (United States)

    Calcagno, Danielle Queiroz; de Arruda Cardoso Smith, Marília; Burbano, Rommel Rodriguez

    2015-01-01

    Gastric cancer (GC) remains a major cause of mortality despite declining rate in the world. Epigenetic alterations contribute significantly to the development and progression of gastric tumors. Epigenetic refers to the number of modifications of the chromatin structure that affect gene expression without altering the primary sequence of DNA, and these changes lead to transcriptional activation or silencing of the gene. Over the years, the study of epigenetic processes has increased, and novel therapeutic approaches have emerged. This chapter summarizes the main epigenomic mechanisms described recently involved in gastric carcinogenesis, focusing on the roles that aberrant DNA methylation, histone modifications (histone acetylation and methylation), and miRNAs (oncogenic and tumor suppressor function of miRNA) play in the onset and progression of gastric tumors. Clinical implications of these epigenetic alterations in GC are also discussed.

  2. Genetic and Epigenetic Mechanisms Linking Pain and Psychiatric Disorders.

    Science.gov (United States)

    Swiergiel, Artur H; Juszczak, Grzegorz R; Stankiewicz, Adrian M

    2015-01-01

    The neurophysiological link between neuropathic pain and depression remains unknown despite evident high comorbidity of these two disorders. However, there is convincing evidence that genotype plays a role in both pain and depression. Using various types of genetic analysis - population genetics, cytogenetics and molecular technologies - specific genes have been implicated in mediating almost all aspects of nociception and mood disorders. The current review attempts to identify specific genes and epigenetic mechanisms common to both disorders. It is concluded that external and internal factors (inflammation, stress, gender, etc.) that contribute to the pathologies may do so through epigenetic mechanisms that may affect expression of these particular genes. The possible involvement of epigenetic regulation in pain and psychiatric disorders suggests that treatments targeting epigenetic mechanisms that mediate adverse life events should be considered. PMID:26436761

  3. 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 ...

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. In utero exposure to carcinogens: Epigenetics, developmental disruption and consequences in later life.

    Science.gov (United States)

    Waring, R H; Harris, R M; Mitchell, S C

    2016-04-01

    The uterine environment is often viewed as a relatively safe haven, being guarded by the placenta which acts as a filter, permitting required materials to enter and unwanted products to be removed. However, this defensive barrier is sometimes breached by potential chemical hazards to which the mother may be subjected. Many of these toxins have immediate and recognisable deleterious effects on the embryo, foetus or neonate, but a few are insidious and leave a legacy of health issues that may emerge in later life. Several substances, falling into the categories of metals and metalloids, endocrine disruptors, solvents and other industrial chemicals, have been implicated in the development of long-term health problems in the offspring following maternal and subsequent in utero exposure. The mechanisms involved are complex but often involve epigenetic changes which disrupt normal cell processes leading to the development of cancers and also dysregulation of biochemical pathways. PMID:26921930

  12. 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.

  13. 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

  14. Insects as models to study the epigenetic basis of disease.

    Science.gov (United States)

    Mukherjee, Krishnendu; Twyman, Richard M; Vilcinskas, Andreas

    2015-07-01

    Epigenetic inheritance refers to changes in gene expression that are heritable across generations but are not caused by changes in the DNA sequence. Many environmental factors are now known to cause epigenetic changes, including the presence of pathogens, parasites, harmful chemicals and other stress factors. There is increasing evidence that transcriptional reprogramming caused by epigenetic modifications can be passed from parents to offspring. Indeed, diseases such as cancer can occur in the offspring due to epigenetically-inherited gene expression profiles induced by stress experienced by the parent. Empirical studies to investigate the role of epigenetics in trans-generational gene regulation and disease require appropriate model organisms. In this review, we argue that selected insects can be used as models for human diseases with an epigenetic component because the underlying molecular mechanisms (DNA methylation, histone acetylation and the expression of microRNAs) are evolutionarily conserved. Insects offer a number of advantages over mammalian models including ethical acceptability, short generation times and the potential to investigate complex interacting parameters such as fecundity, longevity, gender ratio, and resistance to pathogens, parasites and environmental stress.

  15. 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

  16. Epigenetic inheritance in apomictic dandelions

    NARCIS (Netherlands)

    Preite, V.

    2016-01-01

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

  17. [Epigenetic dysregulation in myelodysplastic syndrome].

    Science.gov (United States)

    Sashida, Goro; Iwama, Atsushi

    2015-02-01

    Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by impaired hematopoiesis and an increased risk of transformation to acute myeloid leukemia. Various epigenetic regulators are mutated in MDS patients, indicating that accumulation of epigenetic alterations together with genetic alterations plays a crucial role in the development of MDS.

  18. 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…

  19. 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

  20. Epigenetic mechanisms in epilepsy.

    Science.gov (United States)

    Kobow, Katja; Blümcke, Ingmar

    2014-01-01

    In humans, genomic DNA is organized in 23 chromosome pairs coding for roughly 25,000 genes. Not all of them are active at all times. During development, a broad range of different cell types needs to be generated in a highly ordered and reproducible manner, requiring selective gene expression programs. Epigenetics can be regarded as the information management system that is able to index or bookmark distinct regions in our genome to regulate the readout of DNA. It further comprises the molecular memory of any given cell, allowing it to store information of previously experienced external (e.g., environmental) or internal (e.g., developmental) stimuli, to learn from this experience and to respond. The underlying epigenetic mechanisms can be synergistic, antagonistic, or mutually exclusive and their large variety combined with the variability and interdependence is thought to provide the molecular basis for any phenotypic variation in physiological and pathological conditions. Thus, widespread reconfiguration of the epigenome is not only a key feature of neurodevelopment, brain maturation, and adult brain function but also disease.

  1. 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

  2. Mechanistic studies of cyclohexanone monooxygenase: chemical properties of intermediates involved in catalysis.

    Science.gov (United States)

    Sheng, D; Ballou, D P; Massey, V

    2001-09-18

    Cyclohexanone monooxygenase (CHMO), a bacterial flavoenzyme, carries out an oxygen insertion reaction on cyclohexanone to form a seven-membered cyclic product, epsilon-caprolactone. The reaction catalyzed involves the four-electron reduction of O2 at the expense of a two-electron oxidation of NADPH and a two-electron oxidation of cyclohexanone to form epsilon-caprolactone. Previous studies suggested the participation of either a flavin C4a-hydroperoxide or a flavin C4a-peroxide intermediate during the enzymatic catalysis [Ryerson, C. C., Ballou, D. P., and Walsh, C. (1982) Biochemistry 21, 2644-2655]. However, there was no kinetic or spectral evidence to distinguish between these two possibilities. In the present work we used double-mixing stopped-flow techniques to show that the C4a-flavin-oxygen adduct, which is formed rapidly from the reaction of oxygen with reduced enzyme in the presence of NADP, can exist in two states. When the reaction is carried out at pH 7.2, the first intermediate is a flavin C4a-peroxide with maximum absorbance at 366 nm; this intermediate becomes protonated at about 3 s(-1) to form what is believed to be the flavin C4a-hydroperoxide with maximum absorbance at 383 nm. These two intermediates can be interconverted by altering the pH, with a pK(a) of 8.4. Thus, at pH 9.0 the flavin C4a-peroxide persists mainly in the deprotonated form. Further kinetic studies also demonstrated that only the flavin C4a-peroxide intermediate could oxygenate the substrate, cyclohexanone. The requirement in catalysis of the deprotonated flavin C4a-peroxide, a nucleophile, is consistent with a Baeyer-Villiger rearrangement mechanism for the enzymatic oxygenation of cyclohexanone. In the course of these studies, the Kd for cyclohexanone to the C4a-peroxyflavin form of CHMO was determined to be approximately 1 microM. The rate-determining step in catalysis was shown to be the release of NADP from the oxidized enzyme.

  3. 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

  4. Maintaining epigenetic inheritance during DNA replication in plants

    Directory of Open Access Journals (Sweden)

    Francisco eIglesias

    2016-02-01

    Full Text Available Biotic and abiotic stresses alter the pattern of gene expression in plants. Depending on the frequency and duration of stress events, the effects on the transcriptional state of genes are remembered temporally or transmitted to daughter cells and, in some instances, even to offspring (transgenerational epigenetic inheritance. This memory effect, which can be found even in the absence of the original stress, has an epigenetic basis, through molecular mechanisms that take place at the chromatin and DNA level but do not imply changes in the DNA sequence. Many epigenetic mechanisms have been described and involve covalent modifications on the DNA and histones, such as DNA methylation, histone acetylation and methylation, and RNAi dependent silencing mechanisms. Some of these chromatin modifications need to be stable through cell division in order to be truly epigenetic. During DNA replication, histones are recycled during the formation of the new nucleosomes and this process is tightly regulated. Perturbations to the DNA replication process and/or the recycling of histones lead to epigenetic changes. In this mini-review, we discuss recent evidence aimed at linking DNA replication process to epigenetic inheritance in plants.

  5. Mitochondria in health, aging and diseases: the epigenetic perspective.

    Science.gov (United States)

    D'Aquila, Patrizia; Bellizzi, Dina; Passarino, Giuseppe

    2015-10-01

    The rate/quality of human aging and the development/progression of diseases depend on a complex interplay among genetics, epigenetics and environment. In this scenario, mitochondrial function (or dysfunction) and mitochondrial DNA have emerged as major players. This is mainly due to their crucial role in energetic balance, in modulating epigenetic programs and in influencing cell stress response. Moreover, it is also emerging the existence of epigenetic changes in mitochondrial DNA and of non coding mitochondrial RNAs which, together with the nuclear ones, play regulatory roles in numerous human phenotypes. In this review we will provide an overview on "mitochondrial epigenetics" state of the art, by summarizing the involvement of mitochondrial function and of mitochondria-nucleus communication in regulating nuclear epigenome, as well as the key aspects of the epigenetic marks related to mitochondrial DNA. Despite the limited data available in the literature to date, mainly due to the novelty of the topic, the intriguing interplay of the mitochondrial epigenetic changes in both physiological and pathological conditions will also be presented.

  6. 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.

  7. 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...

  8. 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.

  9. Chemical carcinogenesis

    Directory of Open Access Journals (Sweden)

    Paula A. Oliveira

    2007-12-01

    Full Text Available The use of chemical compounds benefits society in a number of ways. Pesticides, for instance, enable foodstuffs to be produced in sufficient quantities to satisfy the needs of millions of people, a condition that has led to an increase in levels of life expectancy. Yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. Exposure to these compounds can have varying effects, ranging from instant death to a gradual process of chemical carcinogenesis. There are three stages involved in chemical carcinogenesis. These are defined as initiation, promotion and progression. Each of these stages is characterised by morphological and biochemical modifications and result from genetic and/or epigenetic alterations. These genetic modifications include: mutations in genes that control cell proliferation, cell death and DNA repair - i.e. mutations in proto-oncogenes and tumour suppressing genes. The epigenetic factors, also considered as being non-genetic in character, can also contribute to carcinogenesis via epigenetic mechanisms which silence gene expression. The control of responses to carcinogenesis through the application of several chemical, biochemical and biological techniques facilitates the identification of those basic mechanisms involved in neoplasic development. Experimental assays with laboratory animals, epidemiological studies and quick tests enable the identification of carcinogenic compounds, the dissection of many aspects of carcinogenesis, and the establishment of effective strategies to prevent the cancer which results from exposure to chemicals.A sociedade obtém numerosos benefícios da utilização de compostos químicos. A aplicação dos pesticidas, por exemplo, permitiu obter alimento em quantidade suficiente para satisfazer as necessidades alimentares de milhões de pessoas, condição relacionada com o aumento da esperança de vida. Os benefícios estão, por

  10. 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

  11. 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......‐scanning extended X‐ray absorption fine structure spectroscopy enabled the time‐dependent evolution of the starting compound, the intermediates and the product to be monitored over the full reaction period. The reaction starts with fast chlorine substitution and partial reduction during the dissolution...... of the tungsten hexachloride in benzyl alcohol followed by the generation of intermediates with WO double bonds and finally the construction of the WOW network of the tungstite structure....

  12. 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.

  13. 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...

  14. 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...

  15. Epigenetics of sleep and chronobiology.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2014-03-01

    The circadian clock choreographs fundamental biological rhythms. This system is comprised of the master circadian pacemaker in the suprachiasmatic nucleus and associated pacemakers in other tissues that coordinate complex physiological processes and behaviors, such as sleep, feeding, and metabolism. The molecular circuitry that underlies these clocks and orchestrates circadian gene expression has been the focus of intensive investigation, and it is becoming clear that epigenetic factors are highly integrated into these networks. In this review, we draw attention to the fundamental roles played by epigenetic mechanisms in transcriptional and post-transcriptional regulation within the circadian clock system. We also highlight how alterations in epigenetic factors and mechanisms are being linked with sleep-wake disorders. These observations provide important insights into the pathogenesis and potential treatment of these disorders and implicate epigenetic deregulation in the significant but poorly understood interconnections now emerging between circadian processes and neurodegeneration, metabolic diseases, cancer, and aging.

  16. Epigenetics of sleep and chronobiology.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2014-03-01

    The circadian clock choreographs fundamental biological rhythms. This system is comprised of the master circadian pacemaker in the suprachiasmatic nucleus and associated pacemakers in other tissues that coordinate complex physiological processes and behaviors, such as sleep, feeding, and metabolism. The molecular circuitry that underlies these clocks and orchestrates circadian gene expression has been the focus of intensive investigation, and it is becoming clear that epigenetic factors are highly integrated into these networks. In this review, we draw attention to the fundamental roles played by epigenetic mechanisms in transcriptional and post-transcriptional regulation within the circadian clock system. We also highlight how alterations in epigenetic factors and mechanisms are being linked with sleep-wake disorders. These observations provide important insights into the pathogenesis and potential treatment of these disorders and implicate epigenetic deregulation in the significant but poorly understood interconnections now emerging between circadian processes and neurodegeneration, metabolic diseases, cancer, and aging. PMID:24477387

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

    NARCIS (Netherlands)

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

    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 D

  18. 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.

  19. 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

  20. 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.

  1. Exploiting epigenetic vulnerabilities for cancer therapeutics.

    Science.gov (United States)

    Mair, Barbara; Kubicek, Stefan; Nijman, Sebastian M B

    2014-03-01

    Epigenetic deregulation is a hallmark of cancer, and there has been increasing interest in therapeutics that target chromatin-modifying enzymes and other epigenetic regulators. The rationale for applying epigenetic drugs to treat cancer is twofold. First, epigenetic changes are reversible, and drugs could therefore be used to restore the normal (healthy) epigenetic landscape. However, it is unclear whether drugs can faithfully restore the precancerous epigenetic state. Second, chromatin regulators are often mutated in cancer, making them attractive drug targets. However, in most instances it is unknown whether cancer cells are addicted to these mutated chromatin proteins, or whether their mutation merely results in epigenetic instability conducive to the selection of secondary aberrations. An alternative incentive for targeting chromatin regulators is the exploitation of cancer-specific vulnerabilities, including synthetic lethality, caused by epigenetic deregulation. We review evidence for the hypothesis that mechanisms other than oncogene addiction are a basis for the application of epigenetic drugs, and propose future research directions.

  2. 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

  3. 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

  4. Epigenetic mechanisms of gene expression regulation in neurological diseases.

    Science.gov (United States)

    Gos, Monika

    2013-01-01

    Neurological diseases are a heterogenous group of disorders that are related to alterations in nervous system function. The genetic background of neurological diseases is heterogenous and may include chromosomal aberrations, specific gene mutations and epigenetic defects. This review is aimed at presenting of selected diseases that are associated with different epigenetic alterations. The imprinting defects on chromosome 15 are the cause of Prader-Willi and Angelman syndromes that both are characterized by intellectual disability, developmental delay and specific behavioral phenotype. Besides the imprinting defect, these diseases can also be caused by deletion of chromosome 15 or uniparental disomy. Aberrant epigenetic regulation is also specific for Fragile X syndrome that is caused by expansion of CGG repeats in the FMR1 gene that leads to global methylation of the promoter region and repression of FMR1 transcription. A number of neurological diseases, mainly associated with intellectual impairment, may be caused by mutations in genes encoding proteins involved in epigenetic regulation. The number of such diseases is rapidly growing thanks to the implementation of genomic sequencing for the identification of their molecular causes. One of the best known diseases linked to defects in epigenetic modifiers is Rett syndrome caused by a mutation in the MECP2 gene or its variant - Rett-like syndrome caused by a mutation in CDKL5 or FOXG1 genes. As the epigenetic signature is potentially reversible, much attention is focused on possible therapies with drugs that influence DNA or histone modifications. This is especially important in the case of neurological disorders in which epigenetic changes are observed as the effect of the disease.

  5. 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...

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. Carcinogenic effects of circadian disruption: an epigenetic viewpoint.

    Science.gov (United States)

    Salavaty, Abbas

    2015-08-08

    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 modifications and the formation of circadian epigenomes. Aberrant epigenetic modifications, 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 first discuss some of the circadian genes and regulatory proteins. Then, I summarize the current evidence related to the epigenetic modifications 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 viewpoint. Finally, the importance of chronotherapy in cancer treatment is highlighted.

  11. Chiral Antioxidant-based Gold Nanoclusters Reprogram DNA Epigenetic Patterns.

    Science.gov (United States)

    Ma, Yue; Fu, Hualin; Zhang, Chunlei; Cheng, Shangli; Gao, Jie; Wang, Zhen; Jin, Weilin; Conde, João; Cui, Daxiang

    2016-01-01

    Epigenetic modifications sit 'on top of' the genome and influence DNA transcription, which can force a significant impact on cellular behavior and phenotype and, consequently human development and disease. Conventional methods for evaluating epigenetic modifications have inherent limitations and, hence, new methods based on nanoscale devices are needed. Here, we found that antioxidant (glutathione) chiral gold nanoclusters induce a decrease of 5-hydroxymethylcytosine (5hmC), which is an important epigenetic marker that associates with gene transcription regulation. This epigenetic change was triggered partially through ROS activation and oxidation generated by the treatment with glutathione chiral gold nanoclusters, which may inhibit the activity of TET proteins catalyzing the conversion of 5-methylcytosine (5mC) to 5hmC. In addition, these chiral gold nanoclusters can downregulate TET1 and TET2 mRNA expression. Alteration of TET-5hmC signaling will then affect several downstream targets and be involved in many aspects of cell behavior. We demonstrate for the first time that antioxidant-based chiral gold nanomaterials have a direct effect on epigenetic process of TET-5hmC pathways and reveal critical DNA demethylation patterns. PMID:27633378

  12. 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.

  13. Chiral Antioxidant-based Gold Nanoclusters Reprogram DNA Epigenetic Patterns

    Science.gov (United States)

    Ma, Yue; Fu, Hualin; Zhang, Chunlei; Cheng, Shangli; Gao, Jie; Wang, Zhen; Jin, Weilin; Conde, João; Cui, Daxiang

    2016-01-01

    Epigenetic modifications sit ‘on top of’ the genome and influence DNA transcription, which can force a significant impact on cellular behavior and phenotype and, consequently human development and disease. Conventional methods for evaluating epigenetic modifications have inherent limitations and, hence, new methods based on nanoscale devices are needed. Here, we found that antioxidant (glutathione) chiral gold nanoclusters induce a decrease of 5-hydroxymethylcytosine (5hmC), which is an important epigenetic marker that associates with gene transcription regulation. This epigenetic change was triggered partially through ROS activation and oxidation generated by the treatment with glutathione chiral gold nanoclusters, which may inhibit the activity of TET proteins catalyzing the conversion of 5-methylcytosine (5mC) to 5hmC. In addition, these chiral gold nanoclusters can downregulate TET1 and TET2 mRNA expression. Alteration of TET-5hmC signaling will then affect several downstream targets and be involved in many aspects of cell behavior. We demonstrate for the first time that antioxidant-based chiral gold nanomaterials have a direct effect on epigenetic process of TET-5hmC pathways and reveal critical DNA demethylation patterns. PMID:27633378

  14. 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.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. Chemical exposure as etiology in developmental origin of adult onset human cancer

    Directory of Open Access Journals (Sweden)

    Kirsi Vähäkangas

    2011-12-01

    Full Text Available Chemical exposures are in principle preventable causes of cancer. People are exposed to chemicals already during fetal period and the possibility of disturbances in human development by chemical compounds leading to cancer later in life has been proven by diethylstilbestrol. Involved mechanisms most probably include epigenetic modifications of promoter regions of key genes. The world-wide increases in cancer incidence and concurrent increase in the number and quantity of chemicals in the environment raises concerns about a link between these two. Developmental origin and related mechanisms in chemically-induced human cancer are worth pursuing.

  1. 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.

  2. MicroRNAs and DNA methylation as epigenetic regulators of mitosis, meiosis and spermiogenesis.

    Science.gov (United States)

    Yao, Chencheng; Liu, Yun; Sun, Min; Niu, Minghui; Yuan, Qingqing; Hai, Yanan; Guo, Ying; Chen, Zheng; Hou, Jingmei; Liu, Yang; He, Zuping

    2015-07-01

    Spermatogenesis is composed of three distinctive phases, which include self-renewal of spermatogonia via mitosis, spermatocytes undergoing meiosis I/II and post-meiotic development of haploid spermatids via spermiogenesis. Spermatogenesis also involves condensation of chromatin in the spermatid head before transformation of spermatids to spermatozoa. Epigenetic regulation refers to changes of heritably cellular and physiological traits not caused by modifications in the DNA sequences of the chromatin such as mutations. Major advances have been made in the epigenetic regulation of spermatogenesis. In this review, we address the roles and mechanisms of epigenetic regulators, with a focus on the role of microRNAs and DNA methylation during mitosis, meiosis and spermiogenesis. We also highlight issues that deserve attention for further investigation on the epigenetic regulation of spermatogenesis. More importantly, a thorough understanding of the epigenetic regulation in spermatogenesis will provide insightful information into the etiology of some unexplained infertility, offering new approaches for the treatment of male infertility.

  3. Epigenetics: definition, molecular bases and implications in human health and evolution

    Directory of Open Access Journals (Sweden)

    García-Robles Reggie

    2012-04-01

    Full Text Available Epigenetics refers to inheritable changes in DNA and histones that do not involve changes in thesequence of nucleotides and that modifies structure and chromatin condensation, thus affectinggene expression and phenotype. Epigenetic modifications are DNA methylation and histone modifications. Objective: A review of the literature on the concept of Epigenetics and its impacton health. Materials and methods: A review of the literature was performed on the concept ofepigenetics, its biological basis, the impact on health and disease and its relation to evolution.Results: Epigenetic mechanisms have become increasingly important because of the growingassociation with common complex diseases as well as its impact on health of future generationsand in human evolution. Conclusions: Epigenetics has a clear impact on the health of individualsin their offspring and with the evolution of the human species

  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. The cancer epigenome : towards epigenetic therapy

    NARCIS (Netherlands)

    Geutjes, E.J.A.J.

    2011-01-01

    Epigenetic gene silencing occurs in many important biological processes including differentiation, senescence and imprinting. In most cases, epigenetic silencing is orchestrated by an intricate interplay between DNA methylation, histone modifications and nucleosome remodeling that act in concert to

  6. 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.

  7. 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

  8. Epigenetic biomarkers in liver cancer.

    Science.gov (United States)

    Banaudha, Krishna K; Verma, Mukesh

    2015-01-01

    Liver cancer (hepatocellular carcinoma or HCC) is a major cancer worldwide. Research in this field is needed to identify biomarkers that can be used for early detection of the disease as well as new approaches to its treatment. Epigenetic biomarkers provide an opportunity to understand liver cancer etiology and evaluate novel epigenetic inhibitors for treatment. Traditionally, liver cirrhosis, proteomic biomarkers, and the presence of hepatitis viruses have been used for the detection and diagnosis of liver cancer. Promising results from microRNA (miRNA) profiling and hypermethylation of selected genes have raised hopes of identifying new biomarkers. Some of these epigenetic biomarkers may be useful in risk assessment and for screening populations to identify who is likely to develop cancer. Challenges and opportunities in the field are discussed in this chapter.

  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. 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.

  11. 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.

  12. 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.

  13. 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....

  14. 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 ...

  15. Recent Findings in Alzheimer Disease and Nutrition Focusing on Epigenetics.

    Science.gov (United States)

    Athanasopoulos, Dimitrios; Karagiannis, George; Tsolaki, Magda

    2016-09-01

    Alzheimer disease (AD) is a chronic neurodegenerative disease with no effective cure so far. The current review focuses on the epigenetic mechanisms of AD and how nutrition can influence the course of this disease through regulation of gene expression, according to the latest scientific findings. The search strategy was the use of scientific databases such as PubMed and Scopus in order to find relative research or review articles published in the years 2012-2015. By showing the latest data of various nutritional compounds, this study aims to stimulate the scientific community to recognize the value of nutrition in this subject. Epigenetics is becoming a very attractive subject for researchers because it can shed light on unknown aspects of complex diseases like AD. DNA methylation, histone modifications, and microRNAs are the principal epigenetic mechanisms involved in AD pathophysiology. Nutrition is an environmental factor that is related to AD through epigenetic pathways. Vitamin B-12, for instance, can alter the one-carbon metabolism and thus interfere in the DNA methylation process. The research results might seem ambiguous about the clinical role of nutrition, but there is strengthening evidence that proper nutrition can not only change epigenetic biomarker levels but also prevent the development of late-onset AD and attenuate cognition deficit. Nutrition might grow to become a preventive and even therapeutic alternative against AD, especially if combined with other antidementia interventions, brain exercise, physical training, etc. Epigenetic biomarkers can be a very helpful tool to help researchers find the exact nutrients needed to create specific remedies, and perhaps the same biomarkers can be used even in patient screening in the future. PMID:27633107

  16. Epigenetic memory of environmental organisms: a reflection of lifetime stressor exposures.

    Science.gov (United States)

    Mirbahai, Leda; Chipman, James K

    2014-04-01

    Both genetic and epigenetic responses of organisms to environmental factors, including chemical exposures, influence adaptation, susceptibility to toxicity and biodiversity. In model organisms, it is established that epigenetic alterations, including changes to the methylome, can create a memory of the received signal. This is partly evidenced through the analysis of epigenetic differences that develop between identical twins throughout their lifetime. The epigenetic marks induce alterations to the gene expression profile, which, in addition to mediating homeostatic responses, have the potential to promote an abnormal physiology either immediately or at a later stage of development, for example leading to an adult onset of disease. Although this has been well established, epigenetic mechanisms are not considered in chemical risk assessment or utilised in the monitoring of the exposure and effects of chemicals and environmental change. In this review, epigenetic factors, specifically DNA methylation, are highlighted as mechanisms of adaptation and response to environmental factors and which, if persistent, have the potential, retrospectively, to reflect previous stress exposures. Thus, it is proposed that epigenetic "foot-printing" of organisms could identify classes of chemical contaminants to which they have been exposed throughout their lifetime. In some cases, the potential for persistent transgenerational modification of the epigenome may also inform on parental germ cell exposures. It is recommended that epigenetic mechanisms, alongside genetic mechanisms, should eventually be considered in environmental toxicity safety assessments and in biomonitoring studies. This will assist in determining the mode of action of toxicants, no observed adverse effect level and identification of biomarkers of toxicity for early detection and risk assessment in toxicology but there are critical areas that remain to be explored before this can be achieved.

  17. 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

  18. Epigenetic markers to further understand insulin resistance.

    Science.gov (United States)

    Ling, Charlotte; Rönn, Tina

    2016-11-01

    Epigenetic variation in human adipose tissue has been linked to type 2 diabetes and its related risk factors including age and obesity. Insulin resistance, a key risk factor for type 2 diabetes, may also be associated with altered DNA methylation in visceral and subcutaneous adipose tissue. Furthermore, linking epigenetic variation in target tissues to similar changes in blood cells may identify new blood-based biomarkers. In this issue of Diabetologia, Arner et al studied the transcriptome and methylome in subcutaneous and visceral adipose tissue of 80 obese women who were either insulin-sensitive or -resistant (DOI 10.1007/s00125-016-4074-5 ). While they found differences in gene expression between the two groups, no alterations in DNA methylation were found after correction for multiple testing. Nevertheless, based on nominal p values, their methylation data overlapped with methylation differences identified in adipose tissue of individuals with type 2 diabetes compared with healthy individuals. Differential methylation of these overlapping CpG sites may predispose to diabetes by occurring already in the insulin-resistant state. Furthermore, some methylation changes may contribute to an inflammatory process in adipose tissue since the identified CpG sites were annotated to genes encoding proteins involved in inflammation. Finally, the methylation pattern in circulating leucocytes did not mirror the adipose tissue methylome of these 80 women. Together, identifying novel molecular mechanisms contributing to insulin resistance and type 2 diabetes may help advance the search for new therapeutic alternatives. PMID:27650286

  19. 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....

  20. 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...

  1. 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

  2. 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.

  3. 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...

  4. Cytomegalovirus infection accelerates epigenetic aging.

    Science.gov (United States)

    Kananen, Laura; Nevalainen, Tapio; Jylhävä, Juulia; Marttila, Saara; Hervonen, Antti; Jylhä, Marja; Hurme, Mikko

    2015-12-01

    Epigenetic mechanisms such as DNA methylation (DNAm) have a central role in the regulation of gene expression and thereby in cellular differentiation and tissue homeostasis. It has recently been shown that aging is associated with profound changes in DNAm. Several of these methylation changes take place in a clock-like fashion, i.e. correlating with the calendar age of an individual. Thus, the epigenetic clock based on these kind of DNAm changes could provide a new biomarker for human aging process, i.e. being able to separate the calendar and biological age. Information about the correlation of the time indicated by this clock to the various aspects of immunosenescence is still missing. As chronic cytomegalovirus (CMV) infection is probably one of the major driving forces of immunosenescence, we now have analyzed the correlation of CMV seropositivity with the epigenetic age in the Vitality 90+cohort 1920 (122 nonagenarians and 21 young controls, CMV seropositivity rates 95% and 57%, respectively). The data showed that CMV seropositivity was associated with a higher epigenetic age in both of these age groups (median 26.5 vs. 24.0 (p < 0.02,Mann–Whitney U-test) in the young controls and 76.0 vs. 70.0 (p < 0.01) in the nonagenarians). Thus, these data provide a new aspect to the CMV associated pathological processes. PMID:26485162

  5. 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…

  6. 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.

  7. Epigenetics and psychoneuroimmunology: mechanisms and models.

    Science.gov (United States)

    Mathews, Herbert L; Janusek, Linda Witek

    2011-01-01

    In this Introduction to the Named Series "Epigenetics, Brain, Behavior, and Immunity" an overview of epigenetics is provided with a consideration of the nature of epigenetic regulation including DNA methylation, histone modification and chromatin re-modeling. Illustrative examples of recent scientific developments are highlighted to demonstrate the influence of epigenetics in areas of research relevant to those who investigate phenomena within the scientific discipline of psychoneuroimmunology. These examples are presented in order to provide a perspective on how epigenetic analysis will add insight into the molecular processes that connect the brain with behavior, neuroendocrine responsivity and immune outcome.

  8. Epigenetic Modifications: Therapeutic Potential in Cancer

    Directory of Open Access Journals (Sweden)

    Manisha Sachan

    2015-08-01

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

  9. Epigenetic mechanisms: An emerging role in pathogenesis and its therapeutic potential in systemic sclerosis.

    Science.gov (United States)

    Luo, Yangyang; Wang, Yong; Shu, Ye; Lu, Qianjin; Xiao, Rong

    2015-10-01

    Systemic sclerosis (SSc) is a heterogeneous and life-threatening autoimmune disease characterized by damage to small blood vessels, interruption of immune homeostasis and ultimately, fibrosis. Currently, the mechanisms involved in SSc pathogenesis remain unknown. An increasing amount of data shows that, via certain signaling pathways, epigenetic mechanisms, including DNA methylation, histone modification, and miRNAs, are closely related to the three primary processes that characterize SSc: vascular abnormalities, activation of immune system, and excessive extracellular matrix deposition. In the clinical setting, identification of molecules and biomarkers for determining disease severity, predicting disease progression and assessing response to treatment remains challenging. In this review, we aim to summarize the key epigenetic mechanisms involved in the pathogenesis of SSc. Certain cytokines or molecules, such as CD40, CD70, and Fli-1, are expressed at varying rates in SSc due to epigenetic modification and play important roles in SSc. It is therefore likely that these molecules may be biomarkers for SSc. In addition, epigenetic changes of certain genes, including Fli-1, BMPRII, CD11a, Foxp3, and eNOS, influence the expression of these genes to ultimately result in an anti-fibrotic effect. The influence that epigenetics has on SSc pathogenesis suggests that epigenetics-targeting drugs may have potential therapeutic effects against SSc. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.

  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. Transgenerational epigenetic inheritance: an open discussion.

    Science.gov (United States)

    Nagy, Corina; Turecki, Gustavo

    2015-08-01

    Much controversy surrounds the idea of transgenerational epigenetics. Recent papers argue that epigenetic marks acquired through experience are passed to offspring, but as in much of the field of epigenetics, there is lack of precision in the definitions and perhaps too much eagerness to translate animal research to humans. Here, we review operational definitions of transgenerational inheritance and the processes of epigenetic programing during early development. Subsequently, based on this background, we critically examine some recent findings of studies investigating transgenerational inheritance. Finally, we discuss possible mechanisms that may explain transgenerational inheritance, including transmission of an epigenetic blueprint, which may predispose offspring to specific epigenetic patterning. Taken together, we conclude that presently, the evidence suggesting that acquired epigenetic marks are passed to the subsequent generation remains limited.

  13. Epigenetic variation: origin and transgenerational inheritance.

    Science.gov (United States)

    Becker, Claude; Weigel, Detlef

    2012-11-01

    Recent studies have revealed that epigenetic variation in plant populations exceeds genetic diversity and that it is influenced by the environment. Nevertheless, epigenetic differences are not entirely independent of shared ancestry. Epigenetic modifications have gained increasing attention, because one can now study their patterns across the entire genome and in many different individuals. Not only do epigenetic phenomena modulate the activity of the genome in response to environmental stimuli, but they also constitute a potential source of natural variation. Understanding the emergence and heritability of epigenetic variants is critical for understanding how they might become subject to natural selection and thus affect genetic diversity. Here we review progress in characterizing natural epigenetic variants in model and nonmodel plant species and how this work is helping to delineate the role of epigenetic changes in evolution.

  14. Epigenetic regulation of milk production in dairy cows.

    Science.gov (United States)

    Singh, Kuljeet; Erdman, Richard A; Swanson, Kara M; Molenaar, Adrian J; Maqbool, Nauman J; Wheeler, Thomas T; Arias, Juan A; Quinn-Walsh, Erin C; Stelwagen, Kerst

    2010-03-01

    It is well established that milk production of the dairy cow is a function of mammary epithelial cell (MEC) number and activity and that these factors can be influenced by diverse environmental influences and management practises (nutrition, milk frequency, photoperiod, udder health, hormonal and local effectors). Thus, understanding how the mammary gland is able to respond to these environmental cues provides a huge potential to enhance milk production of the dairy cow. In recent years our understanding of molecular events within the MEC underlying bovine lactation has been advanced through mammary microarray studies and will be further advanced through the recent availability of the bovine genome sequence. In addition, the potential of epigenetic regulation (non-sequence inheritable chemical changes in chromatin, such as DNA methylation and histone modifications, which affect gene expression) to manipulate mammary function is emerging. We propose that a substantial proportion of unexplained phenotypic variation in the dairy cow is due to epigenetic regulation. Heritability of epigenetic marks also highlights the potential to modify lactation performance of offspring. Understanding the response of the MEC (cell signaling pathways and epigenetic mechanisms) to external stimuli will be an important prerequisite to devising new technologies for maximising their activity and, hence, milk production in the dairy cow.

  15. 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

  16. [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

  17. Circadian clock: linking epigenetics to aging.

    Science.gov (United States)

    Orozco-Solis, Ricardo; Sassone-Corsi, Paolo

    2014-06-01

    Circadian rhythms are generated by an intrinsic cellular mechanism that controls a large array of physiological and metabolic processes. There is erosion in the robustness of circadian rhythms during aging, and disruption of the clock by genetic ablation of specific genes is associated with aging-related features. Importantly, environmental conditions are thought to modulate the aging process. For example, caloric restriction is a very strong environmental effector capable of delaying aging. Intracellular pathways implicating nutrient sensors, such as SIRTs and mTOR complexes, impinge on cellular and epigenetic mechanisms that control the aging process. Strikingly, accumulating evidences indicate that these pathways are involved in both the modulation of the aging process and the control of the clock. Hence, innovative therapeutic strategies focused at controlling the circadian clock and the nutrient sensing pathways might beneficially influence the negative effects of aging. PMID:25033025

  18. Epigenetics and neuropsychiatric diseases: introduction and meeting summary.

    Science.gov (United States)

    Mehler, Mark F

    2010-09-01

    This volume is an outgrowth of a symposium entitled "Epigenetics and Neuropsychiatric Diseases: Mechanisms Mediating Nature and Nurture" presented at the 88th Annual Conference of the Association for Nervous and Mental Diseases, held on December 5, 2008 at the New York Academy of Medicine. Dolores Malaspina (New York University Medical Center) and Mark F. Mehler (Albert Einstein College of Medicine) organized the symposium as two sessions, "Epigenetics and Brain Behavior Relationships" and "Epigenetics and Neuropsychiatric Diseases." The symposium brought together basic and translational neuroscientists, neurologists, psychiatrists, neuropsychologists, neuropsycho-pharmacologists, and other allied biomedical professionals to establish an enduring dialogue and collaborative interactions concerning epigenetics and epigenomic medicine as a "new science" of brain and behavior relationships. This new discipline has begun to revolutionize our understanding of nervous system development in many specific areas, including neural stem cell biology, fate decisions, and cell diversity and connectivity; learning and memory; neuronal and neural network homeostasis; plasticity and stress responses; the pathogenesis of neuropsychiatric diseases and novel therapeutic interventions involving dynamic cellular reprogramming; reorganization of synaptic and neural network connections; and remodeling of the brain parenchyma and its systemic connections to promote restoration of higher-order cognitive, behavioral, and sensorimotor functions.

  19. The cerebellum ages slowly according to the epigenetic clock.

    Science.gov (United States)

    Horvath, Steve; Mah, Vei; Lu, Ake T; Woo, Jennifer S; Choi, Oi-Wa; Jasinska, Anna J; Riancho, José A; Tung, Spencer; Coles, Natalie S; Braun, Jonathan; Vinters, Harry V; Coles, L Stephen

    2015-05-01

    Studies that elucidate why some human tissues age faster than others may shed light on how we age, and ultimately suggest what interventions may be possible. Here we utilize a recent biomarker of aging (referred to as epigenetic clock) to assess the epigenetic ages of up to 30 anatomic sites from supercentenarians (subjects who reached an age of 110 or older) and younger subjects. Using three novel and three published human DNA methylation data sets, we demonstrate that the cerebellum ages more slowly than other parts of the human body. We used both transcriptional data and genetic data to elucidate molecular mechanisms which may explain this finding. The two largest superfamilies of helicases (SF1 and SF2) are significantly over-represented (p=9.2x10-9) among gene transcripts that are over-expressed in the cerebellum compared to other brain regions from the same subject. Furthermore, SNPs that are associated with epigenetic age acceleration in the cerebellum tend to be located near genes from helicase superfamilies SF1 and SF2 (enrichment p=5.8x10-3). Our genetic and transcriptional studies of epigenetic age acceleration support the hypothesis that the slow aging rate of the cerebellum is due to processes that involve RNA helicases. PMID:26000617

  20. 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 ...

  1. 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...

  2. 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.

  3. 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.

  4. Epigenetics of the antibody response.

    Science.gov (United States)

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

    2013-09-01

    Epigenetic marks, such as DNA methylation, histone post-translational modifications and miRNAs, 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 miRNAs modulate the expression of critical elements of that machinery, such as activation-induced cytidine deaminase (AID), as well as factors central to plasma cell differentiation, such as B lymphocyte-induced maturation protein-1 (Blimp-1). These inducible B cell-intrinsic epigenetic marks instruct the maturation of antibody responses. Their dysregulation plays an important role in aberrant antibody responses to foreign antigens, such as those of microbial pathogens, and self-antigens, such as those targeted in autoimmunity, and B cell neoplasia.

  5. Computational micromodel for epigenetic mechanisms.

    Directory of Open Access Journals (Sweden)

    Karthika Raghavan

    Full Text Available 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.

  6. 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...

  7. Epigenetics of Sleep and Chronobiology

    OpenAIRE

    Qureshi, Irfan A.; Mehler, Mark F.

    2014-01-01

    The circadian clock choreographs fundamental biological rhythms. This system is comprised of the master circadian pacemaker in the suprachiasmatic nucleus and associated pacemakers in other tissues that coordinate complex physiological processes and behaviors, such as sleep, feeding, and metabolism. The molecular circuitry that underlies these clocks and orchestrates circadian gene expression has been the focus of intensive investigation, and it is becoming clear that epigenetic factors are h...

  8. 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).

  9. 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

  10. 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...

  11. 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...

  12. 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

  13. Using Epigenetic Therapy to Overcome Chemotherapy Resistance.

    Science.gov (United States)

    Strauss, Julius; Figg, William D

    2016-01-01

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

  14. The use of epigenetic phenomema for the improvement of sheep and cattle

    Directory of Open Access Journals (Sweden)

    Michael Edward Goddard

    2014-08-01

    Full Text Available This review considers the evidence for inheritance across generations of epigenetic marks and how this phenomenon could be exploited in the cattle and sheep industries. Epigenetic marks are chemical changes in the chromosomes that affect the expression of genes and hence the phenotype of the cell and are passed on during mitosis so that the daughter cells have the same chemical changes or epigenetic marks as the parent cell. Although most epigenetic marks are wiped clean in the process of forming a new zygote, some epigenetic marks (epimutations may be passed on from parent to offspring. The inheritance of epigenetic marks across generations is difficult to prove as there are usually alternative explanations possible. There are few well documented cases, mainly using inbred strains of mice. The epimutations are unstable and revert to wild type after a few generations. Although, there are no known cases in sheep or cattle, it is likely that inherited epimutations occur in these species but it is unlikely that they explain a large part of the inherited or genetic variation. There is limited evidence in mice and rats that an environmental treatment can cause a change in the epigenetic marks of an animal and that this change can be passed on the next generation. If inherited epimutations occur in sheep and cattle, they will already be utilised to some extent by existing genetic improvement programs. It would be possible to modify the statistical models used in the calculation of EBVs to better recognise the variance controlled by epimutations, but it would probably have, at best, a small effect on the rate on genetic (inherited gain achieved. The inheritance of epigenetic marks caused by the environment experienced by the sire offers a new opportunity in sheep and cattle breeding. However, at present we do not know if this occurs or, if it does, what environmental treatment might have a beneficial effect.

  15. 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 ...

  16. 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...

  17. 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.

  18. 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

  19. Obesity: epigenetic regulation – recent observations.

    Science.gov (United States)

    Remely, Marlene; de la Garza, Ana Laura; Magnet, Ulrich; Aumueller, Eva; Haslberger, Alexander G

    2015-06-01

    Genetic and environmental factors, especially nutrition and lifestyle, have been discussed in the literature for their relevance to epidemic obesity. Gene-environment interactions may need to be understood for an improved understanding of the causes of obesity, and epigenetic mechanisms are of special importance. Consequences of epigenetic mechanisms seem to be particularly important during certain periods of life: prenatal, postnatal and intergenerational, transgenerational inheritance are discussed with relevance to obesity. This review focuses on nutrients, diet and habits influencing intergenerational, transgenerational, prenatal and postnatal epigenetics; on evidence of epigenetic modifiers in adulthood; and on animal models for the study of obesity.

  20. Transcriptomic analysis of the GCN5 gene reveals mechanisms of the epigenetic regulation of virulence and morphogenesis in Ustilago maydis.

    Science.gov (United States)

    Martínez-Soto, Domingo; González-Prieto, Juan Manuel; Ruiz-Herrera, José

    2015-09-01

    Chromatin in the eukaryotic nucleus is highly organized in the form of nucleosomes where histones wrap DNA. This structure may be altered by some chemical modifications of histones, one of them, acetylation by histone acetyltransferases (HATs) that originates relaxation of the nucleosome structure, providing access to different transcription factors and other effectors. In this way, HATs regulate cellular processes including DNA replication, and gene transcription. Previously, we isolated Ustilago maydis mutants deficient in the GCN5 HAT that are avirulent, and grow constitutively as mycelium. In this work, we proceeded to identify the genes differentially regulated by GCN5, comparing the transcriptomes of the mutant and the wild type using microarrays, to analyse the epigenetic control of virulence and morphogenesis. We identified 1203 genes, 574 positively and 629 negatively regulated in the wild type. We found that genes belonging to different categories involved in pathogenesis were downregulated in the mutant, and that genes involved in mycelial growth were negatively regulated in the wild type, offering a working hypothesis on the epigenetic control of virulence and morphogenesis of U. maydis. Interestingly, several differentially regulated genes appeared in clusters, suggesting a common regulation. Some of these belonged to pathogenesis or secondary metabolism.

  1. 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...

  2. 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

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

    Directory of Open Access Journals (Sweden)

    Stefano Nardone

    2016-07-01

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

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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.

  9. 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...

  10. Epigenetic regulation of pluripotency and differentiation.

    Science.gov (United States)

    Boland, Michael J; Nazor, Kristopher L; Loring, Jeanne F

    2014-07-01

    The precise, temporal order of gene expression during development is critical to ensure proper lineage commitment, cell fate determination, and ultimately, organogenesis. Epigenetic regulation of chromatin structure is fundamental to the activation or repression of genes during embryonic development. In recent years, there has been an explosion of research relating to various modes of epigenetic regulation, such as DNA methylation, post-translational histone tail modifications, noncoding RNA control of chromatin structure, and nucleosome remodeling. Technological advances in genome-wide epigenetic profiling and pluripotent stem cell differentiation have been primary drivers for elucidating the epigenetic control of cellular identity during development and nuclear reprogramming. Not only do epigenetic mechanisms regulate transcriptional states in a cell-type-specific manner but also they establish higher order genomic topology and nuclear architecture. Here, we review the epigenetic control of pluripotency and changes associated with pluripotent stem cell differentiation. We focus on DNA methylation, DNA demethylation, and common histone tail modifications. Finally, we briefly discuss epigenetic heterogeneity among pluripotent stem cell lines and the influence of epigenetic patterns on genome topology.

  11. Epigenetic variation in asexually reproducing organisms

    NARCIS (Netherlands)

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

    2014-01-01

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

  12. 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...

  13. 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...

  14. 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

  15. 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 ...

  16. 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

  17. Epigenetic mechanisms in migraine: a promising avenue?

    Science.gov (United States)

    Eising, Else; A Datson, Nicole; van den Maagdenberg, Arn M J M; Ferrari, Michel D

    2013-01-01

    Migraine is a disabling common brain disorder typically characterized by attacks of severe headache and associated with autonomic and neurological symptoms. Its etiology is far from resolved. This review will focus on evidence that epigenetic mechanisms play an important role in disease etiology. Epigenetics comprise both DNA methylation and post-translational modifications of the tails of histone proteins, affecting chromatin structure and gene expression. Besides playing a role in establishing cellular and developmental stage-specific regulation of gene expression, epigenetic processes are also important for programming lasting cellular responses to environmental signals. Epigenetic mechanisms may explain how non-genetic endogenous and exogenous factors such as female sex hormones, stress hormones and inflammation trigger may modulate attack frequency. Developing drugs that specifically target epigenetic mechanisms may open up exciting new avenues for the prophylactic treatment of migraine.

  18. 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...

  19. Epigenetics and therapeutic targets mediating neuroprotection.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2015-12-01

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

  20. 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.

  1. 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

  2. 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

  3. Entropy production in a chemical system involving an autocatalytic reaction in an isothermal, continuous stirred tank reactor

    Science.gov (United States)

    Yoshida, Nobuo

    1990-02-01

    The rate of entropy production due to chemical reaction is calculated for various combinations of parameter values in the cubic autocatalator model in an isothermal, continuous stirred tank reactor (CSTR) proposed by Gray and Scott and by Escher and Ross. Values of the entropy production averaged over periods of limit cycle oscillations are compared with those in coexistent unstable stationary states. It is found that in ranges of the residence time over which there are limit cycles, the entropy production in coexisting stationary states increases as the residence time is shortened, i.e., as the system is removed farther from thermodynamic equilibrium. The average entropy production over a limit cycle is less than that in the corresponding stationary state over wide ranges of parameter values, but not necessarily for the whole oscillatory region. More specifically, the former inequality always prevails in ranges where the entropy production of stationary states is larger, i.e., the residence time is shorter, but in some cases the inequality is reversed in ranges of lower magnitudes of the entropy production.

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. 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.

  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. [Advances of Epigenetic Studies on Mechanisms of Paramutation].

    Science.gov (United States)

    Cheng, Shan; Wang, Xiao-Rong; Ding, Wei

    2016-02-01

    Studies in traditional genetics have revealed the molecular causes of many genetic diseases and provided direct clues for their prevention, diagnosis and treatments, as well as for various disorders with genetic background. However, the genetic profiles of most human diseases could not be fully explained with the canonical laws of genetics. Paramutation is one of non-Mendelian inheritance phenomenon, which was found in maize first in 1950s. The absence of alteration in nucleotide sequences in the gene-coding alleles suggested that paramutations might involve epigenetic mechanisms to transmit heritable changes in gene expression and determination of phenotypes. Recently, a novel epigenetic mechanism has been found in paramutation researches, emphasized the importance of DNA methyltransferase II mediated RNA (primarily non-coding RNAs) methylation in the occurrence and maintenance of paramutations. Researches on paramutations and their epigenetic mechnisms will not only expand our understanding in the genetic principles of life, but also help to develop new ideas for bioengineer and disease treatments. The present article reviewed the research highlights on molecular mechanisms of paramutation and discussed the prospects in disease study and therapy.

  11. 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.

  12. Potential roles of noncoding RNAs in environmental epigenetic transgenerational inheritance.

    Science.gov (United States)

    Yan, Wei

    2014-12-01

    "Epigenetic transgenerational inheritance" (ETI) has been defined as germline (sperm or egg) transmission of epigenetic information between generations in the absence of direct exposures or genetic manipulations. Among reported cases of ETI in mammals, the majority are induced by environmental factors, including environmental toxicants [e.g. agricultural fungicide vinclozolin, plastic additive bisphenol A, pesticide methoxychlor, dioxin, di-(2-ethylhexyl) phthalate, dichlorodiphenyltrichloroethane, and hydrocarbons] and poor nutritional conditions. Although the ETI phenomenon is well established, the underlying mechanism remains elusive. Putative epimutations, including changes in DNA methylation and histone modification patterns, have been reported, but it remains unclear how these epimutations are formed in the first place, and how they are memorized in the germline and then get transmitted to subsequent generations. Based on recent advances in our understanding of regulatory noncoding RNAs (ncRNAs), I propose that ncRNAs are involved in ETI, during both the initial epimutation formation and the subsequent germline transmission of epimutations. ncRNAs can function at epigenetic levels by affecting DNA methylation and histone modifications, thereby changing gene transcriptional activities, which can lead to an altered mRNA transcriptome associated with a disease phenotype. Alternatively, novel or altered ncRNA expression can cause dysregulated post-transcriptional regulation, thus directly affecting the mRNA transcriptome and inducing a disease phenotype. Sperm-borne ncRNAs are potential mediators for epigenetic memory across generations, but they alone may not be sufficient for stable transmission of epimutations across generations. Overall, research on ncRNAs in the context of ETI is urgently needed to shed light on the underlying mechanism of ETI.

  13. Epigenetics and autoimmune diseases: the X chromosome-nucleolus nexus.

    Science.gov (United States)

    Brooks, Wesley H; Renaudineau, Yves

    2015-01-01

    Autoimmune diseases occur more often in females, suggesting a key role for the X chromosome. X chromosome inactivation, a major epigenetic feature in female cells that provides dosage compensation of X-linked genes to avoid overexpression, presents special vulnerabilities that can contribute to the disease process. Disruption of X inactivation can result in loss of dosage compensation with expression from previously sequestered genes, imbalance of gene products, and altered endogenous material out of normal epigenetic context. In addition, the human X has significant differences compared to other species and these differences can contribute to the frequency and intensity of the autoimmune disease in humans as well as the types of autoantigens encountered. Here a link is demonstrated between autoimmune diseases, such as systemic lupus erythematosus, and the X chromosome by discussing cases in which typically non-autoimmune disorders complicated with X chromosome abnormalities also present lupus-like symptoms. The discussion is then extended to the reported spatial and temporal associations of the inactive X chromosome with the nucleolus. When frequent episodes of cellular stress occur, the inactive X chromosome may be disrupted and inadvertently become involved in the nucleolar stress response. Development of autoantigens, many of which are at least transiently components of the nucleolus, is then described. Polyamines, which aid in nucleoprotein complex assembly in the nucleolus, increase further during cell stress, and appear to have an important role in the autoimmune disease process. Autoantigenic endogenous material can potentially be stabilized by polyamines. This presents a new paradigm for autoimmune diseases: that many are antigen-driven and the autoantigens originate from altered endogenous material due to episodes of cellular stress that disrupt epigenetic control. This suggests that epigenetics and the X chromosome are important aspects of autoimmune

  14. Small RNA-directed epigenetic natural variation in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Jixian Zhai

    2008-04-01

    Full Text Available Progress in epigenetics has revealed mechanisms that can heritably regulate gene function independent of genetic alterations. Nevertheless, little is known about the role of epigenetics in evolution. This is due in part to scant data on epigenetic variation among natural populations. In plants, small interfering RNA (siRNA is involved in both the initiation and maintenance of gene silencing by directing DNA methylation and/or histone methylation. Here, we report that, in the model plant Arabidopsis thaliana, a cluster of approximately 24 nt siRNAs found at high levels in the ecotype Landsberg erecta (Ler could direct DNA methylation and heterochromatinization at a hAT element adjacent to the promoter of FLOWERING LOCUS C (FLC, a major repressor of flowering, whereas the same hAT element in ecotype Columbia (Col with almost identical DNA sequence, generates a set of low abundance siRNAs that do not direct these activities. We have called this hAT element MPF for Methylated region near Promoter of FLC, although de novo methylation triggered by an inverted repeat transgene at this region in Col does not alter its FLC expression. DNA methylation of the Ler allele MPF is dependent on genes in known silencing pathways, and such methylation is transmissible to Col by genetic crosses, although with varying degrees of penetrance. A genome-wide comparison of Ler and Col small RNAs identified at least 68 loci matched by a significant level of approximately 24 nt siRNAs present specifically in Ler but not Col, where nearly half of the loci are related to repeat or TE sequences. Methylation analysis revealed that 88% of the examined loci (37 out of 42 were specifically methylated in Ler but not Col, suggesting that small RNA can direct epigenetic differences between two closely related Arabidopsis ecotypes.

  15. 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.

  16. 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.

  17. 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.

  18. The emerging role of epigenetics in pulmonary arterial hypertension: an important avenue for clinical trials (2015 Grover Conference Series).

    Science.gov (United States)

    Huston, Jessica H; Ryan, John J

    2016-09-01

    Epigenetics is an emerging field of research and clinical trials in cancer therapy that also has applications for pulmonary arterial hypertension (PAH), as there is evidence that epigenetic control of gene expression plays a significant role in PAH. The three types of epigenetic modification include DNA methylation, histone modification, and RNA interference. All three have been shown to be involved in the development of PAH. Currently, the enzymes that perform these modifications are the primary targets of neoplastic therapy. These targets are starting to be explored for therapies in PAH, mostly in animal models. In this review we summarize the basics of each type of epigenetic modification and the known sites and molecules involved in PAH, as well as current targets and prospects for clinical trials. PMID:27683604

  19. Epigenetic Modifications in Neurological Diseases: Natural Products as Epigenetic Modulators a Treatment Strategy.

    Science.gov (United States)

    Gangisetty, Omkaram; Murugan, Sengottuvelan

    2016-01-01

    Epigenetic modifications, including DNA methylation, covalent histone modifications, and small noncoding RNAs, play a key role in regulating the gene expression. This regulatory mechanism is important in cellular differentiation and development. Recent advances in the field of epigenetics extended the role of epigenetic mechanisms in controlling key biological processes such as genome imprinting and X-chromosome inactivation. Aberrant epigenetic modifications are associated with the development of many diseases. The role of epigenetic modifications in various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington disease, epilepsy, and multiple sclerosis is rapidly emerging. The use of epigenetic modifying drugs to treat these diseases has been the interest in recent years. A number of natural products having diverse mechanism of action are used for drug discovery. For many years, natural compounds have been used to treat various neurodegenerative diseases, but the use of such compounds as epigenetic modulators to reverse or treat neurological diseases are not well studied. In this chapter, we mainly focus on how various epigenetic modifications play a key role in neurodegenerative diseases, their mechanism of action, and how it acts as a potential therapeutic target for epigenetic drugs to treat these diseases will be discussed.

  20. Epigenetic Modifications in Neurological Diseases: Natural Products as Epigenetic Modulators a Treatment Strategy.

    Science.gov (United States)

    Gangisetty, Omkaram; Murugan, Sengottuvelan

    2016-01-01

    Epigenetic modifications, including DNA methylation, covalent histone modifications, and small noncoding RNAs, play a key role in regulating the gene expression. This regulatory mechanism is important in cellular differentiation and development. Recent advances in the field of epigenetics extended the role of epigenetic mechanisms in controlling key biological processes such as genome imprinting and X-chromosome inactivation. Aberrant epigenetic modifications are associated with the development of many diseases. The role of epigenetic modifications in various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington disease, epilepsy, and multiple sclerosis is rapidly emerging. The use of epigenetic modifying drugs to treat these diseases has been the interest in recent years. A number of natural products having diverse mechanism of action are used for drug discovery. For many years, natural compounds have been used to treat various neurodegenerative diseases, but the use of such compounds as epigenetic modulators to reverse or treat neurological diseases are not well studied. In this chapter, we mainly focus on how various epigenetic modifications play a key role in neurodegenerative diseases, their mechanism of action, and how it acts as a potential therapeutic target for epigenetic drugs to treat these diseases will be discussed. PMID:27651245

  1. 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

  2. Epigenetic variation, phenotypic heritability, and evolution

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  3. 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...

  4. Transgenerational epigenetic inheritance in health and disease.

    Science.gov (United States)

    Whitelaw, Nadia C; Whitelaw, Emma

    2008-06-01

    Over the past century, patterns of phenotypic inheritance have been observed that are not easily rationalised by Mendel's rules of inheritance. Now that we have begun to understand more about non-DNA based, or 'epigenetic', control of phenotype at the molecular level, the idea that the transgenerational inheritance of these epigenetic states could explain non-Mendelian patterns of inheritance has become attractive. There is a growing body of evidence that abnormal epigenetic states, termed epimutations, are associated with disease in humans. For example, in several cases of colorectal cancer, epimutations have been identified that silence the human mismatch repair genes, MLH1 and MSH2. But strong evidence that the abnormal epigenetic states are primary events that occur in the absence of genetic change and are inherited across generations is still absent.

  5. Epigenetic Effects of Di(2-ethylhexyl) Phthalate

    Science.gov (United States)

    Epidemiological and laboratory investigations suggest that, in addition to genetic changes, environmental pollutants can affect human health through altering epigenetic mechanisms including DNA methylation, histone modification, and microRNA expression. There is evidence in anima...

  6. 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 

  7. 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...

  8. 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, ...

  9. 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.

  10. 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 ...

  11. 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

  12. Conference scene: Select Biosciences Epigenetics Europe 2010.

    Science.gov (United States)

    Razvi, Enal S

    2011-02-01

    The field of epigenetics is now on a geometric rise, driven in a large part by the realization that modifiers of chromatin are key regulators of biological processes in vivo. The three major classes of epigenetic effectors are DNA methylation, histone post-translational modifications (such as acetylation, methylation or phosphorylation) and small noncoding RNAs (most notably microRNAs). In this article, I report from Select Biosciences Epigenetics Europe 2010 industry conference held on 14-15 September 2010 at The Burlington Hotel, Dublin, Ireland. This industry conference was extremely well attended with a global pool of delegates representing the academic research community, biotechnology companies and pharmaceutical companies, as well as the technology/tool developers. This conference represented the current state of the epigenetics community with cancer/oncology as a key driver. In fact, it has been estimated that approximately 45% of epigenetic researchers today identify cancer/oncology as their main area of focus vis-à-vis their epigenetic research efforts. PMID:22126149

  13. 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.

  14. 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

  15. Inhibitors of emerging epigenetic targets for cancer therapy: a patent review (2010-2014).

    Science.gov (United States)

    Tanaka, Minoru; Roberts, Justin M; Qi, Jun; Bradner, James E

    2015-01-01

    Gene regulatory pathways comprise an emerging and active area of chemical probe discovery and investigational drug development. Emerging insights from cancer genome sequencing and chromatin biology have identified leveraged opportunities for development of chromatin-directed small molecules as cancer therapies. At present, only six agents in two epigenetic target classes have been approved by the US FDA, limited to treatment of hematological malignancies. Recently, new classes of epigenetic inhibitors have appeared in literatures. First-in-class compounds have successfully transitioned to clinical investigation, importantly also in solid tumors and pediatric malignancies. This review considers patent applications for small-molecule inhibitors of selected epigenetic targets from 2010 to 2014. Included are exemplary classes of chromatin-associated epigenomic writers (DOT1L and EZH2), erasers (LSD1) and readers (BRD4).

  16. Epigenetic silencing of Plasmodium falciparum genes linked to erythrocyte invasion.

    Directory of Open Access Journals (Sweden)

    Alfred Cortés

    2007-08-01

    Full Text Available The process of erythrocyte invasion by merozoites of Plasmodium falciparum involves multiple steps, including the formation of a moving junction between parasite and host cell, and it is characterised by the redundancy of many of the receptor-ligand interactions involved. Several parasite proteins that interact with erythrocyte receptors or participate in other steps of invasion are encoded by small subtelomerically located gene families of four to seven members. We report here that members of the eba, rhoph1/clag, acbp, and pfRh multigene families exist in either an active or a silenced state. In the case of two members of the rhoph1/clag family, clag3.1 and clag3.2, expression was mutually exclusive. Silencing was clonally transmitted and occurred in the absence of detectable DNA alterations, suggesting that it is epigenetic. This was demonstrated for eba-140. Our data demonstrate that variant or mutually exclusive expression and epigenetic silencing in Plasmodium are not unique to genes such as var, which encode proteins that are exported to the surface of the erythrocyte, but also occur for genes involved in host cell invasion. Clonal variant expression of invasion-related ligands increases the flexibility of the parasite to adapt to its human host.

  17. 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

  18. 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.

  19. 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 cap...

  20. 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…

  1. 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

  2. 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.

  3. X-linked mental retardation and epigenetics.

    Science.gov (United States)

    Froyen, Guy; Bauters, Marijke; Voet, Thierry; Marynen, Peter

    2006-01-01

    The search for the genetic defects in constitutional diseases has so far been restricted to direct methods for the identification of genetic mutations in the patients' genome. Traditional methods such as karyotyping, FISH, mutation screening, positional cloning and CGH, have been complemented with newer methods including array-CGH and PCR-based approaches (MLPA, qPCR). These methods have revealed a high number of genetic or genomic aberrations that result in an altered expression or reduced functional activity of key proteins. For a significant percentage of patients with congenital disease however, the underlying cause has not been resolved strongly suggesting that yet other mechanisms could play important roles in their etiology. Alterations of the 'native' epigenetic imprint might constitute such a novel mechanism. Epigenetics, heritable changes that do not rely on the nucleotide sequence, has already been shown to play a determining role in embryonic development, X-inactivation, and cell differentiation in mammals. Recent progress in the development of techniques to study these processes on full genome scale has stimulated researchers to investigate the role of epigenetic modifications in cancer as well as in constitutional diseases. We will focus on mental impairment because of the growing evidence for the contribution of epigenetics in memory formation and cognition. Disturbance of the epigenetic profile due to direct alterations at genomic regions, or failure of the epigenetic machinery due to genetic mutations in one of its components, has been demonstrated in cognitive derangements in a number of neurological disorders now. It is therefore tempting to speculate that the cognitive deficit in a significant percentage of patients with unexplained mental retardation results from epigenetic modifications.

  4. 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.

  5. Transgenerational epigenetic imprinting of the male germline by endocrine disruptor exposure during gonadal sex determination.

    Science.gov (United States)

    Chang, Hung-Shu; Anway, Matthew D; Rekow, Stephen S; Skinner, Michael K

    2006-12-01

    Embryonic exposure to the endocrine disruptor vinclozolin at the time of gonadal sex determination was previously found to promote transgenerational disease states. The actions of vinclozolin appear to be due to epigenetic alterations in the male germline that are transmitted to subsequent generations. Analysis of the transgenerational epigenetic effects on the male germline (i.e. sperm) identified 25 candidate DNA sequences with altered methylation patterns in the vinclozolin generation sperm. These sequences were identified and mapped to specific genes and noncoding DNA regions. Bisulfite sequencing was used to confirm the altered methylation pattern of 15 of the candidate DNA sequences. Alterations in the epigenetic pattern (i.e. methylation) of these genes/DNA sequences were found in the F2 and F3 generation germline. Therefore, the reprogramming of the male germline involves the induction of new imprinted-like genes/DNA sequences that acquire an apparent permanent DNA methylation pattern that is passed at least through the paternal allele. The expression pattern of several of the genes during embryonic development were found to be altered in the vinclozolin F1 and F2 generation testis. A number of the imprinted-like genes/DNA sequences identified are associated with epigenetic linked diseases. In summary, an endocrine disruptor exposure during embryonic gonadal sex determination was found to promote an alteration in the epigenetic (i.e. induction of imprinted-like genes/DNA sequences) programming of the male germline, and this is associated with the development of transgenerational disease states.

  6. 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

  7. Krebs cycle intermediates regulate DNA and histone methylation: epigenetic impact on the aging process.

    Science.gov (United States)

    Salminen, Antero; Kauppinen, Anu; Hiltunen, Mikko; Kaarniranta, Kai

    2014-07-01

    Many aging theories have proposed that mitochondria and energy metabolism have a major role in the aging process. There are recent studies indicating that Krebs cycle intermediates can shape the epigenetic landscape of chromatin by regulating DNA and histone methylation. A growing evidence indicates that epigenetics plays an important role in the regulation of healthspan but also is involved in the aging process. 2-Oxoglutarate (α-ketoglutarate) is a key metabolite in the Krebs cycle but it is also an obligatory substrate for 2-oxoglutarate-dependent dioxygenases (2-OGDO). The 2-OGDO enzyme family includes the major enzymes of DNA and histone demethylation, i.e. Ten-Eleven Translocation (TETs) and Jumonji C domain containing (JmjC) demethylases. In addition, 2-OGDO members can regulate collagen synthesis and hypoxic responses in a non-epigenetical manner. Interestingly, succinate and fumarate, also Krebs cycle intermediates, are potent inhibitors of 2-OGDO enzymes, i.e. the balance of Krebs cycle reactions can affect the level of DNA and histone methylation and thus control gene expression. We will review the epigenetic mechanisms through which Krebs cycle intermediates control the DNA and histone methylation. We propose that age-related disturbances in the Krebs cycle function induce stochastic epigenetic changes in chromatin structures which in turn promote the aging process.

  8. Widespread Epigenetic Abnormalities Suggest a Broad DNA Methylation Erasure Defect in Abnormal Human Sperm

    Science.gov (United States)

    Siegmund, Kimberly; Yang, Allen; Laird, Peter W.; Sokol, Rebecca Z.

    2007-01-01

    Background Male-factor infertility is a common condition, and etiology is unknown for a high proportion of cases. Abnormal epigenetic programming of the germline is proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. During germ cell maturation and gametogenesis, cells of the germ line undergo extensive epigenetic reprogramming. This process involves widespread erasure of somatic-like patterns of DNA methylation followed by establishment of sex-specific patterns by de novo DNA methylation. Incomplete reprogramming of the male germ line could, in theory, result in both altered sperm DNA methylation and compromised spermatogenesis. Methodology/Principal Finding We determined concentration, motility and morphology of sperm in semen samples collected by male members of couples attending an infertility clinic. Using MethyLight and Illumina assays we measured methylation of DNA isolated from purified sperm from the same samples. Methylation at numerous sequences was elevated in DNA from poor quality sperm. Conclusions This is the first report of a broad epigenetic defect associated with abnormal semen parameters. Our results suggest that the underlying mechanism for these epigenetic changes may be improper erasure of DNA methylation during epigenetic reprogramming of the male germ line. PMID:18074014

  9. Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm.

    Directory of Open Access Journals (Sweden)

    Sahar Houshdaran

    Full Text Available BACKGROUND: Male-factor infertility is a common condition, and etiology is unknown for a high proportion of cases. Abnormal epigenetic programming of the germline is proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. During germ cell maturation and gametogenesis, cells of the germ line undergo extensive epigenetic reprogramming. This process involves widespread erasure of somatic-like patterns of DNA methylation followed by establishment of sex-specific patterns by de novo DNA methylation. Incomplete reprogramming of the male germ line could, in theory, result in both altered sperm DNA methylation and compromised spermatogenesis. METHODOLOGY/PRINCIPAL FINDING: We determined concentration, motility and morphology of sperm in semen samples collected by male members of couples attending an infertility clinic. Using MethyLight and Illumina assays we measured methylation of DNA isolated from purified sperm from the same samples. Methylation at numerous sequences was elevated in DNA from poor quality sperm. CONCLUSIONS: This is the first report of a broad epigenetic defect associated with abnormal semen parameters. Our results suggest that the underlying mechanism for these epigenetic changes may be improper erasure of DNA methylation during epigenetic reprogramming of the male germ line.

  10. 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. 

  11. 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. 

  12. The epigenetic control of hepatitis B virus modulates the outcome of infection

    Directory of Open Access Journals (Sweden)

    Lemonica eKoumbi

    2016-01-01

    Full Text Available Epigenetic modifications are stable alterations in gene expression that do not involve mutations of the genetic sequence itself. It has become increasingly clear that epigenetic factors contribute to the outcome of chronic hepatitis B virus (HBV infection by affecting cellular and virion gene expression, viral replication and the development of hepatocellular carcinoma. HBV persists in the nucleus of infected hepatocytes as a stable non-integrated covalently closed circular DNA (cccDNA which functions as a minichromosome. There are two major forms of HBV epigenetic regulation: posttranslational modification of histone proteins associated with the cccDNA minichromosome and DNA methylation of viral and host genomes. This review explores how HBV can interphase with host epigenetic regulation in order to evade host defences and to promote its own survival and persistence. We focus on the effect of cccDNA bound-histone modifications and the methylation status of HBV DNA in regulating viral replication. Investigation of HBV epigenetic control has important clinical correlates with regards to the development of potential therapeutic regimens that will successfully eradicate HBV infection and deal with HBV reactivation in those undergoing treatment with demethylating agents.

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. Obesity accelerates epigenetic aging of human liver.

    Science.gov (United States)

    Horvath, Steve; Erhart, Wiebke; Brosch, Mario; Ammerpohl, Ole; von Schönfels, Witigo; Ahrens, Markus; Heits, Nils; Bell, Jordana T; Tsai, Pei-Chien; Spector, Tim D; Deloukas, Panos; Siebert, Reiner; Sipos, Bence; Becker, Thomas; Röcken, Christoph; Schafmayer, Clemens; Hampe, Jochen

    2014-10-28

    Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an "epigenetic clock") to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver (r = 0.42, P = 6.8 × 10(-4) in dataset 1 and r = 0.42, P = 1.2 × 10(-4) in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10(-9)) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer. PMID:25313081

  19. 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

  20. 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.

  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. Age-associated epigenetic drift: implications, and a case of epigenetic thrift?

    Science.gov (United States)

    Teschendorff, Andrew E; West, James; Beck, Stephan

    2013-10-15

    It is now well established that the genomic landscape of DNA methylation (DNAm) gets altered as a function of age, a process we here call 'epigenetic drift'. The biological, functional, clinical and evolutionary significance of this epigenetic drift, however, remains unclear. We here provide a brief review of epigenetic drift, focusing on the potential implications for ageing, stem cell biology and disease risk prediction. It has been demonstrated that epigenetic drift affects most of the genome, suggesting a global deregulation of DNAm patterns with age. A component of this drift is tissue-specific, allowing remarkably accurate age-predictive models to be constructed. Another component is tissue-independent, targeting stem cell differentiation pathways and affecting stem cells, which may explain the observed decline of stem cell function with age. Age-associated increases in DNAm target developmental genes, overlapping those associated with environmental disease risk factors and with disease itself, notably cancer. In particular, cancers and precursor cancer lesions exhibit aggravated age DNAm signatures. Epigenetic drift is also influenced by genetic factors. Thus, drift emerges as a promising biomarker for premature or biological ageing, and could potentially be used in geriatrics for disease risk prediction. Finally, we propose, in the context of human evolution, that epigenetic drift may represent a case of epigenetic thrift, or bet-hedging. In summary, this review demonstrates the growing importance of the 'ageing epigenome', with potentially far-reaching implications for understanding the effect of age on stem cell function and differentiation, as well as for disease prevention.

  3. Current status and future prospects for epigenetic psychopharmacology

    NARCIS (Netherlands)

    Boks, Marco P; de Jong, Noëlle M; Kas, Martien J H; Vinkers, Christiaan H; Fernandes, Cathy; Kahn, René S; Mill, Jonathan; Ophoff, Roel A

    2012-01-01

    Mounting evidence suggest that epigenetic regulation of brain functions is important in the etiology of psychiatric disorders. These epigenetic regulatory mechanisms, such as DNA methylation and histone acetylation, are influenced by many pharmaceutical compounds including psychiatric drugs. It is t

  4. 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

  5. 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...

  6. 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

  7. Diagnostic and prognostic epigenetic biomarkers in cancer.

    Science.gov (United States)

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

    2015-01-01

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

  8. 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

  9. Epigenetic Regulation of Adaptive NK Cell Diversification.

    Science.gov (United States)

    Tesi, Bianca; Schlums, Heinrich; Cichocki, Frank; Bryceson, Yenan T

    2016-07-01

    Natural killer (NK) cells were previously considered to represent short-lived, innate lymphocytes. However, mouse models have revealed expansion and persistence of differentiated NK cell subsets in response to cytomegalovirus (CMV) infection, paralleling antigen-specific T cell differentiation. Congruently, analyses of humans have uncovered CMV-associated NK cell subsets characterized by epigenetic diversification processes that lead to altered target cell specificities and functional capacities. Here, focusing on responses to viruses, we review similarities and differences between mouse and human adaptive NK cells, identifying molecular analogies that may be key to transcriptional reprogramming and functional alterations. We discuss possible molecular mechanisms underlying epigenetic diversification and hypothesize that processes driving epigenetic diversification may represent a more widespread mechanism for fine-tuning and optimization of cellular immunity.

  10. 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

  11. Gene-Environment Interactions in Asthma: Genetic and Epigenetic Effects.

    Science.gov (United States)

    Lee, Jong-Uk; Kim, Jeong Dong; Park, Choon-Sik

    2015-07-01

    Over the past three decades, a large number of genetic studies have been aimed at finding genetic variants associated with the risk of asthma, applying various genetic and genomic approaches including linkage analysis, candidate gene polymorphism studies, and genome-wide association studies (GWAS). However, contrary to general expectation, even single nucleotide polymorphisms (SNPs) discovered by GWAS failed to fully explain the heritability of asthma. Thus, application of rare allele polymorphisms in well defined phenotypes and clarification of environmental factors have been suggested to overcome the problem of 'missing' heritability. Such factors include allergens, cigarette smoke, air pollutants, and infectious agents during pre- and post-natal periods. The first and simplest interaction between a gene and the environment is a candidate interaction of both a well known gene and environmental factor in a direct physical or chemical interaction such as between CD14 and endotoxin or between HLA and allergens. Several GWAS have found environmental interactions with occupational asthma, aspirin exacerbated respiratory disease, tobacco smoke-related airway dysfunction, and farm-related atopic diseases. As one of the mechanisms behind gene-environment interaction is epigenetics, a few studies on DNA CpG methylation have been reported on subphenotypes of asthma, pitching the exciting idea that it may be possible to intervene at the junction between the genome and the environment. Epigenetic studies are starting to include data from clinical samples, which will make them another powerful tool for re-search on gene-environment interactions in asthma.

  12. 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.

  13. 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.

  14. [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

  15. Obesity accelerates epigenetic aging of human liver

    OpenAIRE

    Horvath, S.; Erhart, W.; Brosch, M; Ammerpohl, O; von Schonfels, W.; Ahrens, M.; Heits, N; Bell, J. T.; Tsai, P.-C.; Spector, T.D.; Deloukas, P.; Siebert, R.; Sipos, B.; Becker, T.; C. Rocken

    2014-01-01

    Because obese people are at an increased risk of many age-related diseases, it is a plausible hypothesis that obesity increases the biological age of some tissues and cell types. However, it has been difficult to detect such an accelerated aging effect because it is unclear how to measure tissue age. Here we use a recently developed biomarker of aging (known as “epigenetic clock”) to study the relationship between epigenetic age and obesity in several human tissues. We report an unexpectedly ...

  16. 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.

  17. 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...

  18. 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.

  19. Epigenetic dynamics in psychiatric disorders : Environmental programming of neurodevelopmental processes

    NARCIS (Netherlands)

    Kofink, Daniel; Boks, Marco P. M.; Timmers, H. T. Marc; Kas, Martien J.

    2013-01-01

    Epigenetic processes have profound influence on gene translation and play a key role in embryonic development and tissue type specification. Recent advances in our understanding of epigenetics have pointed out that epigenetic alterations also play an important role in neurodevelopment and may increa

  20. Epigenetic dynamics in psychiatric disorders : environmental programming of neurodevelopmental processes

    NARCIS (Netherlands)

    Kofink, Daniel; Boks, Marco P M; Timmers, H T Marc; Kas, Martien J

    2013-01-01

    Epigenetic processes have profound influence on gene translation and play a key role in embryonic development and tissue type specification. Recent advances in our understanding of epigenetics have pointed out that epigenetic alterations also play an important role in neurodevelopment and may increa

  1. 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…

  2. 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.

  3. Identification of genomic features in environmentally induced epigenetic transgenerational inherited sperm epimutations.

    Directory of Open Access Journals (Sweden)

    Carlos Guerrero-Bosagna

    Full Text Available A variety of environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. The process involves exposure of a gestating female and the developing fetus to environmental factors that promote permanent alterations in the epigenetic programming of the germline. The molecular aspects of the phenomenon involve epigenetic modifications (epimutations in the germline (e.g. sperm that are transmitted to subsequent generations. The current study integrates previously described experimental epigenomic transgenerational data and web-based bioinformatic analyses to identify genomic features associated with these transgenerationally transmitted epimutations. A previously identified genomic feature associated with these epimutations is a low CpG density (<12/100bp. The current observations suggest the transgenerational differential DNA methylation regions (DMR in sperm contain unique consensus DNA sequence motifs, zinc finger motifs and G-quadruplex sequences. Interaction of molecular factors with these sequences could alter chromatin structure and accessibility of proteins with DNA methyltransferases to alter de novo DNA methylation patterns. G-quadruplex regions can promote the opening of the chromatin that may influence the action of DNA methyltransferases, or factors interacting with them, for the establishment of epigenetic marks. Zinc finger binding factors can also promote this chromatin remodeling and influence the expression of non-coding RNA. The current study identified genomic features associated with sperm epimutations that may explain in part how these sites become susceptible for transgenerational programming.

  4. Identification of genomic features in environmentally induced epigenetic transgenerational inherited sperm epimutations.

    Science.gov (United States)

    Guerrero-Bosagna, Carlos; Weeks, Shelby; Skinner, Michael K

    2014-01-01

    A variety of environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. The process involves exposure of a gestating female and the developing fetus to environmental factors that promote permanent alterations in the epigenetic programming of the germline. The molecular aspects of the phenomenon involve epigenetic modifications (epimutations) in the germline (e.g. sperm) that are transmitted to subsequent generations. The current study integrates previously described experimental epigenomic transgenerational data and web-based bioinformatic analyses to identify genomic features associated with these transgenerationally transmitted epimutations. A previously identified genomic feature associated with these epimutations is a low CpG density (transgenerational differential DNA methylation regions (DMR) in sperm contain unique consensus DNA sequence motifs, zinc finger motifs and G-quadruplex sequences. Interaction of molecular factors with these sequences could alter chromatin structure and accessibility of proteins with DNA methyltransferases to alter de novo DNA methylation patterns. G-quadruplex regions can promote the opening of the chromatin that may influence the action of DNA methyltransferases, or factors interacting with them, for the establishment of epigenetic marks. Zinc finger binding factors can also promote this chromatin remodeling and influence the expression of non-coding RNA. The current study identified genomic features associated with sperm epimutations that may explain in part how these sites become susceptible for transgenerational programming.

  5. 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.

  6. p300 exerts an epigenetic role in chronic neuropathic pain through its acetyltransferase activity in rats following chronic constriction injury (CCI

    Directory of Open Access Journals (Sweden)

    Zhu Xiao-Yan

    2012-11-01

    Full Text Available Abstract Background Neuropathic pain is detrimental to human health; however, its pathogenesis still remains largely unknown. Overexpression of pain-associated genes and increased nociceptive somato-sensitivity are well observed in neuropathic pain. The importance of epigenetic mechanisms in regulating the expression of pro- or anti-nociceptive genes has been revealed by studies recently, and we hypothesize that the transcriptional coactivator and the histone acetyltransferase E1A binding protein p300 (p300, as a part of the epigenetic mechanisms of gene regulation, may be involved in the pathogenesis of neuropathic pain induced by chronic constriction injury (CCI. To test this hypothesis, two different approaches were used in this study: (I down-regulating p300 with specific small hairpin RNA (shRNA and (II chemical inhibition of p300 acetyltransferase activity by a small molecule inhibitor, C646. Results Using the CCI rat model, we found that the p300 expression was increased in the lumbar spinal cord on day 14 after CCI. The treatment with intrathecal p300 shRNA reversed CCI-induced mechanical allodynia and thermal hyperalgesia, and suppressed the expression of cyclooxygenase-2 (COX-2, a neuropathic pain-associated factor. Furthermore, C646, an inhibitor of p300 acetyltransferase, also attenuated mechanical allodynia and thermal hyperalgesia, accompanied by a suppressed COX-2 expression, in the spinal cord. Conclusions The results suggest that, through its acetyltransferase activity in the spinal cord after CCI, p300 epigenetically plays an important role in neuropathic pain. Inhibiting p300, using interfering RNA or C646, may be a promising approach to the development of new neuropathic pain therapies.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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...

  12. 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

  13. Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation.

    Science.gov (United States)

    Herceg, Zdenko; Lambert, Marie-Pierre; van Veldhoven, Karin; Demetriou, Christiana; Vineis, Paolo; Smith, Martyn T; Straif, Kurt; Wild, Christopher P

    2013-09-01

    Remarkable progress in the field of epigenetics has turned academic, medical and public attention to the potential applications of these new advances in medicine and various fields of biomedical research. The result is a broader appreciation of epigenetic phenomena in the a etiology of common human diseases, most notably cancer. These advances also represent an exciting opportunity to incorporate epigenetics and epigenomics into carcinogen identification and safety assessment. Current epigenetic studies, including major international sequencing projects, are expected to generate information for establishing the 'normal' epigenome of tissues and cell types as well as the physiological variability of the epigenome against which carcinogen exposure can be assessed. Recently, epigenetic events have emerged as key mechanisms in cancer development, and while our search of the Monograph Volume 100 revealed that epigenetics have played a modest role in evaluating human carcinogens by the International Agency for Research on Cancer (IARC) Monographs so far, epigenetic data might play a pivotal role in the future. Here, we review (i) the current status of incorporation of epigenetics in carcinogen evaluation in the IARC Monographs Programme, (ii) potential modes of action for epigenetic carcinogens, (iii) current in vivo and in vitro technologies to detect epigenetic carcinogens, (iv) genomic regions and epigenetic modifications and their biological consequences and (v) critical technological and biological issues in assessment of epigenetic carcinogens. We also discuss the issues related to opportunities and challenges in the application of epigenetic testing in carcinogen identification and evaluation. Although the application of epigenetic assays in carcinogen evaluation is still in its infancy, important data are being generated and valuable scientific resources are being established that should catalyse future applications of epigenetic testing.

  14. 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.

  15. DNA Methylation, Epigenetics, and Evolution in Vertebrates: Facts and Challenges

    Directory of Open Access Journals (Sweden)

    Annalisa Varriale

    2014-01-01

    Full Text Available DNA methylation is a key epigenetic modification in the vertebrate genomes known to be involved in biological processes such as regulation of gene expression, DNA structure and control of transposable elements. Despite increasing knowledge about DNA methylation, we still lack a complete understanding of its specific functions and correlation with environment and gene expression in diverse organisms. To understand how global DNA methylation levels changed under environmental influence during vertebrate evolution, we analyzed its distribution pattern along the whole genome in mammals, reptiles and fishes showing that it is correlated with temperature, independently on phylogenetic inheritance. Other studies in mammals and plants have evidenced that environmental stimuli can promote epigenetic changes that, in turn, might generate localized changes in DNA sequence resulting in phenotypic effects. All these observations suggest that environment can affect the epigenome of vertebrates by generating hugely different methylation patterns that could, possibly, reflect in phenotypic differences. We are at the first steps towards the understanding of mechanisms that underlie the role of environment in molding the entire genome over evolutionary times. The next challenge will be to map similarities and differences of DNA methylation in vertebrates and to associate them with environmental adaptation and evolution.

  16. 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

  17. A longitudinal study of epigenetic variation in twins

    Science.gov (United States)

    Caspi, Avshalom; Williams, Benjamin; Craig, Ian W; Houts, Renate; Ambler, Antony; Moffitt, Terrie E; Mill, Jonathan

    2010-01-01

    DNA methylation is a key epigenetic mechanism involved in the developmental regulation of gene expression. Alterations in DNA methylation are established contributors to inter-individual phenotypic variation and have been associated with disease susceptibility. The degree to which changes in loci-specific DNA methylation are under the influence of heritable and environmental factors is largely unknown. In this study, we quantitatively measured DNA methylation across the promoter regions of the dopamine receptor 4 gene (DRD4), the serotonin transporter gene (SLC6A4/SERT) and the X-linked monoamine oxidase A gene (MAOA) using DNA sampled at both ages 5 and 10 years in 46 MZ twinpairs and 45 DZ twin-pairs (total n = 182). Our data suggest that DNA methylation differences are apparent already in early childhood, even between genetically identical individuals, and that individual differences in methylation are not stable over time. Our longitudinal-developmental study suggests that environmental influences are important factors accounting for interindividual DNA methylation differences, and that these influences differ across the genome. The observation of dynamic changes in DNA methylation over time highlights the importance of longitudinal research designs for epigenetic research. PMID:20505345

  18. Epigenetic: a molecular link between testicular cancer and environmental exposures?

    Directory of Open Access Journals (Sweden)

    Aurelie eVega

    2012-11-01

    Full Text Available In the last decades, studies in rodents have highlighted links between in utero and/or neonatal exposures to molecules that alter endocrine functions and the development of genital tract abnormalities, such as cryptorchidism, hypospadias, and impaired spermatogenesis. Most of these molecules, called endocrine disrupters (EDs exert estrogenic and/or antiandrogenic activities. These data led to the hypothesis of the Testicular Dysgenesis Syndrome which postulates that these disorders are one clinical entity and are linked by epidemiological and pathophysiological relations. Futhermore, infertility has been stated as a risk factor for testicular cancer. The incidence of testicular cancer has been increasing over the past decades. Most of testicular germ cell cancers develop through a pre-invasive carcinoma in situ (CIS from fetal germ cells (primordial germ cell or gonocyte. During their development, fetal germ cells undergo epigenetic modifications. Interestingly, several lines of evidence have shown that gene regulation through epigenetic mechanisms (DNA and histone modifications plays an important role in normal development as well as in various diseases, including testicular cancer.Here we will review chromatin modifications which can affect testicular physiology leading to the development of testicular cancer; and highlight potential molecular pathways involved in these alterations in the context of environmental exposures.

  19. 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) ...

  20. 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

  1. Epigenetics of osteoarticular diseases: recent developments.

    Science.gov (United States)

    Roberts, S B; Wootton, E; De Ferrari, L; Albagha, O M; Salter, D M

    2015-08-01

    A variety of osteoarticular conditions possess an underlying genetic aetiology. Large-scale genome-wide association studies have identified several genetic loci associated with osteoarticular conditions, but were unable to fully account for their estimated heritability. Epigenetic modifications including DNA methylation, histone modification, nucleosome positioning, and microRNA expression may help account for this incomplete heritability. This articles reviews insights from epigenetic studies in osteoarticular diseases, focusing on osteoarthritis, but also examines recent advances in rheumatoid arthritis, osteoporosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, and sarcoma. Genome-wide methylation studies are permitting identification of novel candidate genes and molecular pathways, and the pathogenic mechanisms with altered methylation status are beginning to be elucidated. These findings are gradually translating into improved understanding of disease pathogenesis and clinical applications. Functional studies in osteoarthritis, rheumatoid arthritis, and SLE are now identifying downstream molecular alterations that may confer disease susceptibility. Epigenetic markers are being validated as prognostic and therapeutic disease biomarkers in sarcoma, and clinical trials of hypomethylating agents as treatments for sarcoma are being conducted. In concert with advances in throughput and cost-efficiency of available technologies, future epigenetic research will enable greater characterisation and treatment for both common and rare osteoarticular diseases.

  2. 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

  3. Epigenetic mechanisms governing the process of neurodegeneration.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2013-01-01

    Studies elucidating how and why neurodegeneration unfolds suggest that a complex interplay between genetic and environmental factors is responsible for disease pathogenesis. Recent breakthroughs in the field of epigenetics promise to advance our understanding of these mechanisms and to promote the development of useful and effective pre-clinical risk stratification strategies, molecular diagnostic and prognostic methods, and disease-modifying treatments.

  4. 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.

  5. 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

  6. Phenotype as Agent for Epigenetic Inheritance

    Directory of Open Access Journals (Sweden)

    John S. Torday

    2016-07-01

    Full Text Available 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.

  7. 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.

  8. 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.

  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. 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...

  11. 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…

  12. The Epigenetic Effects of Prenatal Cadmium Exposure.

    Science.gov (United States)

    Vilahur, Nadia; Vahter, Marie; Broberg, Karin

    2015-06-01

    Prenatal exposure to the highly toxic and common pollutant cadmium has been associated with adverse effects on child health and development. However, the underlying biological mechanisms of cadmium toxicity remain partially unsolved. Epigenetic disruption due to early cadmium exposure has gained attention as a plausible mode of action, since epigenetic signatures respond to environmental stimuli and the fetus undergoes drastic epigenomic rearrangements during embryogenesis. In the current review, we provide a critical examination of the literature addressing prenatal cadmium exposure and epigenetic effects in human, animal, and in vitro studies. We conducted a PubMed search and obtained eight recent studies addressing this topic, focusing almost exclusively on DNA methylation. These studies provide evidence that cadmium alters epigenetic signatures in the DNA of the placenta and of the newborns, and some studies indicated marked sexual differences for cadmium-related DNA methylation changes. Associations between early cadmium exposure and DNA methylation might reflect interference with de novo DNA methyltransferases. More studies, especially those including environmentally relevant doses, are needed to confirm the toxicoepigenomic effects of prenatal cadmium exposure and how that relates to the observed health effects of cadmium in childhood and later life.

  13. 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...

  14. 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.

  15. 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...

  16. 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

  17. 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....

  18. 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.

  19. 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

  20. Epigenetic modulators as therapeutic targets in prostate cancer.

    Science.gov (United States)

    Graça, Inês; Pereira-Silva, Eva; Henrique, Rui; Packham, Graham; Crabb, Simon J; Jerónimo, Carmen

    2016-01-01

    Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management. PMID:27651838

  1. 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...

  2. Targeted transcriptional activation of silent oct4 pluripotency gene by combining designer TALEs and inhibition of epigenetic modifiers.

    Science.gov (United States)

    Bultmann, Sebastian; Morbitzer, Robert; Schmidt, Christine S; Thanisch, Katharina; Spada, Fabio; Elsaesser, Janett; Lahaye, Thomas; Leonhardt, Heinrich

    2012-07-01

    Specific control of gene activity is a valuable tool to study and engineer cellular functions. Recent studies uncovered the potential of transcription activator-like effector (TALE) proteins that can be tailored to activate user-defined target genes. It remains however unclear whether and how epigenetic modifications interfere with TALE-mediated transcriptional activation. We studied the activity of five designer TALEs (dTALEs) targeting the oct4 pluripotency gene. In vitro assays showed that the five dTALEs that target distinct sites in the oct4 promoter had the expected DNA specificity and comparable affinities to their corresponding DNA targets. In contrast to their similar in vitro properties, transcriptional activation of oct4 by these distinct dTALEs varied up to 25-fold. While dTALEs efficiently upregulated transcription of the active oct4 promoter in embryonic stem cells (ESCs) they failed to activate the silenced oct4 promoter in ESC-derived neural stem cells (NSCs), indicating that as for endogenous transcription factors also dTALE activity is limited by repressive epigenetic mechanisms. We therefore targeted the activity of epigenetic modulators and found that chemical inhibition of histone deacetylases by valproic acid or DNA methyltransferases by 5-aza-2'-deoxycytidine facilitated dTALE-mediated activation of the epigenetically silenced oct4 promoter in NSCs. Notably, demethylation of the oct4 promoter occurred only if chemical inhibitors and dTALEs were applied together but not upon treatment with inhibitors or dTALEs only. These results show that dTALEs in combination with chemical manipulation of epigenetic modifiers facilitate targeted transcriptional activation of epigenetically silenced target genes.

  3. 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

  4. Polyketide Production of Pestaloficiols and Macrodiolide Ficiolides Revealed by Manipulations of Epigenetic Regulators in an Endophytic Fungus.

    Science.gov (United States)

    Wu, Guangwei; Zhou, Haichuan; Zhang, Peng; Wang, Xiuna; Li, Wei; Zhang, Weiwei; Liu, Xingzhong; Liu, Hong-Wei; Keller, Nancy P; An, Zhiqiang; Yin, Wen-Bing

    2016-04-15

    Regarding targeted disruption of epigenetic regulators, histone methyltransferase and deacetylase in a plant endophytic fungus Pestalotiopsis fici have been uncovered as an unexplored chemical repertoire. Manipulation of epigenetic regulators led to the isolation of 15 new polyketides, including pestaloficiols T-W (1-3 and 5), as well as 11 macrodiolide ficiolides A-K (6-16). Ficiolide K (16) was found to contain a very rare 1,6-anhydro-pyranose moiety. Finally, the biosynthetic origin of macrodiolide was characterized by isotope-labeling experiments.

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. Berberine acts as a putative epigenetic modulator by affecting the histone code.

    Science.gov (United States)

    Wang, Zhixiang; Liu, Yuan; Xue, Yong; Hu, Haiyan; Ye, Jieyu; Li, Xiaodong; Lu, Zhigang; Meng, Fanyi; Liang, Shuang

    2016-10-01

    Berberine, an isoquinoline plant alkaloid, exhibits a wide range of biochemical and pharmacological effects. However, the precise mechanism of these bioactivities remains poorly understood. In this study, we found significant similarity between berberine and two epigenetic modulators (CG-1521 and TSA). Reverse-docking using berberine as a ligand identified lysine-N-methyltransferase as a putative target of berberine. These findings suggested the potential role of berberine in epigenetic modulation. The results of PCR array analysis of epigenetic chromatin modification enzymes supported our hypothesis. Furthermore, the analysis showed that enzymes involved in histone acetylation and methylation were predominantly affected by treatment with berberine. Up-regulation of histone acetyltransferase CREBBP and EP300, histone deacetylase SIRT3, histone demethylase KDM6A as well as histone methyltransferase SETD7, and down-regulation of histone acetyltransferase HDAC8, histone methyltransferase WHSC1I, WHSC1II and SMYD3, in addition to 38 genes from histone clusters 1-3 were observed in berberine-treated cells using real-time PCR. In parallel, western blotting analyses revealed that the expression of H3K4me3, H3K27me3 and H3K36me3 proteins decreased with berberine treatment. These results were further confirmed in acute myelocytic leukemia (AML) cell lines HL-60/ADR and KG1-α. Taken together, this study suggests that berberine might modulate the expression of epigenetic regulators important for many downstream pathways, resulting in the variation of its bioactivities. PMID:27311644

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

    Directory of Open Access Journals (Sweden)

    Bui Ha TN

    2010-11-01

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

  11. 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?

  12. 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

  13. 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

  14. 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.

  15. Genomic patterns of DNA methylation: targets and function of an epigenetic mark.

    Science.gov (United States)

    Weber, Michael; Schübeler, Dirk

    2007-06-01

    Methylation of cytosines can mediate epigenetic gene silencing and is the only known DNA modification in eukaryotes. Recent efforts to map DNA methylation across mammalian genomes revealed limited DNA methylation at regulatory regions but widespread methylation in intergenic regions and repeats. This is consistent with the idea that hypermethylation is the default epigenetic state and serves in maintaining genome integrity. DNA methylation patterns at regulatory regions are generally stable, but a minor subset of regulatory regions show variable DNA methylation between cell types, suggesting an additional dynamic component. Such promoter de novo methylation might be involved in the maintenance rather than the initiation of silencing of defined genes during development. How frequently such dynamic methylation occurs, its biological relevance and the pathways involved deserve investigation. PMID:17466503

  16. Epigenetic Modifications of Major Depressive Disorder.

    Science.gov (United States)

    Saavedra, Kathleen; Molina-Márquez, Ana María; Saavedra, Nicolás; Zambrano, Tomás; Salazar, Luis A

    2016-01-01

    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. PMID:27527165

  17. 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.

  18. 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.

  19. 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...

  20. 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...

  1. 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...

  2. 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

  3. Accelerated epigenetic aging in Down syndrome

    OpenAIRE

    Horvath, Steve; Garagnani, Paolo; Bacalini, Maria Giulia; Pirazzini, Chiara; Salvioli, Stefano; Gentilini, Davide; Di Blasio, Anna Maria; Giuliani, Cristina; Tung, Spencer; Vinters, Harry V.; Franceschi, Claudio

    2015-01-01

    Down Syndrome (DS) entails an increased risk of many chronic diseases that are typically associated with older age. The clinical manifestations of accelerated aging suggest that trisomy 21 increases the biological age of tissues, but molecular evidence for this hypothesis has been sparse. Here, we utilize a quantitative molecular marker of aging (known as the epigenetic clock) to demonstrate that trisomy 21 significantly increases the age of blood and brain tissue (on average by 6.6 years, P ...

  4. 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

  5. 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

  6. [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.

  7. 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

  8. Developmental epigenetics of the murine secondary palate.

    Science.gov (United States)

    Seelan, Ratnam S; Mukhopadhyay, Partha; Pisano, M Michele; Greene, Robert M

    2012-01-01

    Orofacial clefts occur with a frequency of 1 to 2 per 1000 live births. Cleft palate, which accounts for 30% of orofacial clefts, is caused by the failure of the secondary palatal processes--medially directed, oral projections of the paired embryonic maxillary processes--to fuse. Both gene mutations and environmental effects contribute to the complex etiology of this disorder. Although much progress has been made in identifying genes whose mutations are associated with cleft palate, little is known about the mechanisms by which the environment adversely influences gene expression during secondary palate development. An increasing body of evidence, however, implicates epigenetic processes as playing a role in adversely influencing orofacial development. Epigenetics refers to inherited changes in phenotype or gene expression caused by processes other than changes in the underlying DNA sequence. Such processes include, but are not limited to, DNA methylation, microRNA effects, and histone modifications that alter chromatin conformation. In this review, we describe our current understanding of the possible role epigenetics may play during development of the secondary palate. Specifically, we present the salient features of the embryonic palatal methylome and profile the expression of numerous microRNAs that regulate protein-encoding genes crucial to normal orofacial ontogeny.

  9. Epigenetic mechanisms in cardiac development and disease

    Institute of Scientific and Technical Information of China (English)

    Marcus Vallaster; Caroline Dacwag Vallaster; Sean M. Wu

    2012-01-01

    During mammalian development,cardiac specification and ultimately lineage commitment to a specific cardiac cell type is accomplished by the action of specific transcription factors (TFs) and their meticulous control on an epigenetic level.In this review,we detail how cardiacspecific TFs function in concert with nucleosome remodeling and histone-modifying enzymes to regulate a diverse network of genes required for processes such as cell growth and proliferation,or epithelial to mesenchymal transition (EMT),for instance.We provide examples of how several cardiac TFs,such as Nkx2.5,WHSC1,Tbx5,and Tbx1,which are associated with developmental and congenital heart defects,are required for the recruitment of histone modifiers,such as Jarid2,p300,and Ash21,and components of ATP-dependent remodeling enzymes like Brg1,Baf60c,and Baf180.Binding of these TFs to their respective sites at cardiac genes coincides with a distinct pattern of histone marks,indicating that the precise regulation of cardiac gene networks is orchestrated by interactions between TFs and epigenetic modifiers.Furthermore,we speculate that an epigenetic signature,comprised of TF occupancy,histone modifications,and overall chromatin organization,is an underlying mechanism that governs cardiac morphogenesis and disease.

  10. 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.

  11. 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)

  12. 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...

  13. The prima donna of epigenetics: the regulation of gene expression by DNA methylation

    Directory of Open Access Journals (Sweden)

    K.F. Santos

    2005-10-01

    Full Text Available This review focuses on the mechanisms of DNA methylation, DNA methylation pattern formation and their involvement in gene regulation. Association of DNA methylation with imprinting, embryonic development and human diseases is discussed. Furthermore, besides considering changes in DNA methylation as mechanisms of disease, the role of epigenetics in general and DNA methylation in particular in transgenerational carcinogenesis, in memory formation and behavior establishment are brought about as mechanisms based on the cellular memory of gene expression patterns.

  14. 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...

  15. 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...

  16. 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...

  17. 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

  18. Transgenerational Epigenetic Contributions to Stress Responses: Fact or Fiction?

    Directory of Open Access Journals (Sweden)

    Eric J Nestler

    2016-03-01

    Full Text Available There has been increasing interest in the possibility that behavioral experience--in particular, exposure to stress--can be passed on to subsequent generations through heritable epigenetic modifications. The possibility remains highly controversial, however, reflecting the lack of standardized definitions of epigenetics and the limited empirical support for potential mechanisms of transgenerational epigenetic inheritance. Nonetheless, growing evidence supports a role for epigenetic regulation as a key mechanism underlying lifelong regulation of gene expression that mediates stress vulnerability. This Perspective provides an overview of the multiple meanings of the term epigenetic, discusses the challenges of studying epigenetic contributions to stress susceptibility--and the experimental evidence for and against the existence of such mechanisms--and outlines steps required for future investigations.

  19. 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.

  20. Epigenetic diet: impact on the epigenome and cancer.

    Science.gov (United States)

    Hardy, Tabitha M; Tollefsbol, Trygve O

    2011-08-01

    A number of bioactive dietary components are of particular interest in the field of epigenetics. Many of these compounds display anticancer properties and may play a role in cancer prevention. Numerous studies suggest that a number of nutritional compounds have epigenetic targets in cancer cells. Importantly, emerging evidence strongly suggests that consumption of dietary agents can alter normal epigenetic states as well as reverse abnormal gene activation or silencing. Epigenetic modifications induced by bioactive dietary compounds are thought to be beneficial. Substantial evidence is mounting proclaiming that commonly consumed bioactive dietary factors act to modify the epigenome and may be incorporated into an 'epigenetic diet'. Bioactive nutritional components of an epigenetic diet may be incorporated into one's regular dietary regimen and used therapeutically for medicinal or chemopreventive purposes. This article will primarily focus on dietary factors that have been demonstrated to influence the epigenome and that may be used in conjunction with other cancer prevention and chemotherapeutic therapies.

  1. Role of Epigenetics in Biology and Human Diseases.

    Science.gov (United States)

    Moosavi, Azam; Motevalizadeh Ardekani, Ali

    2016-11-01

    For a long time, scientists have tried to describe disorders just by genetic or environmental factors. However, the role of epigenetics in human diseases has been considered from a half of century ago. In the last decade, this subject has attracted many interests, especially in complicated disorders such as behavior plasticity, memory, cancer, autoimmune disease, and addiction as well as neurodegenerative and psychological disorders. This review first explains the history and classification of epigenetic modifications, and then the role of epigenetic in biology and connection between the epigenetics and environment are explained. Furthermore, the role of epigenetics in human diseases is considered by focusing on some diseases with some complicated features, and at the end, we have given the future perspective of this field. The present review article provides concepts with some examples to reveal a broad view of different aspects of epigenetics in biology and human diseases. PMID:27377127

  2. 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.

  3. Epigenetic suppression of neprilysin regulates breast cancer invasion

    Science.gov (United States)

    Stephen, H M; Khoury, R J; Majmudar, P R; Blaylock, T; Hawkins, K; Salama, M S; Scott, M D; Cosminsky, B; Utreja, N K; Britt, J; Conway, R E

    2016-01-01

    In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT–PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer

  4. 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

  5. The epigenetics of obesity: Role of diet and exercise on adipose, skeletal muscle, and placental tissue metabolism

    Science.gov (United States)

    Maternal undernutrition or consumption of excess food energy contributes to the subsequent development of obesity in offspring. This phenomenon, in part, involves the epigenetic transmission of obesity risk across generations. The primary aim of our study is to determine whether a maternal diet incr...

  6. 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

  7. Epigenetic therapy in gastrointestinal cancer: the right combination

    Science.gov (United States)

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

    2016-01-01

    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

  8. 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...

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. Developing epigenetic diagnostics and therapeutics for brain disorders.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2013-12-01

    Perturbations in epigenetic mechanisms have emerged as cardinal features in the molecular pathology of major classes of brain disorders. We therefore highlight evidence which suggests that specific epigenetic signatures measurable in central - and possibly even in peripheral tissues - have significant value as translatable biomarkers for screening, early diagnosis, and prognostication; developing molecularly targeted medicines; and monitoring disease progression and treatment responses. We also draw attention to existing and novel therapeutic approaches directed at epigenetic factors and mechanisms, including strategies for modulating enzymes that write and erase DNA methylation and histone/chromatin marks; protein-protein interactions responsible for reading epigenetic marks; and non-coding RNA pathways.

  14. Heterosis and combining ability analysis for grain quality and physico-chemical traits involving fertility restorers with basmati background in Rice (Oryza sativa L.

    Directory of Open Access Journals (Sweden)

    Ashok K Sarial

    2014-12-01

    Full Text Available A study was undertaken to explore possibility of developing hybrids and analyze them for heterosis and combining ability for basmati grain and physico-chemical attributes. Initially 45 improved germplasm lines of aromatic and non-aromatic genotypes were test crossed with four cytoplasmic male sterile (CMS lines viz; IR 58025A, IR62829A, PMS10A and PMS 3A of wild abortive cytosterile source to identify basmati pollen parents restoring fertility. Ninteen pollen restorers of basmati background were identified and crossed with 4 CMS lines in line x tester design and analysed for heterosis and combining ability. Observations were recorded for grain quality characteristics viz; hulling percentage, milling percentage and head rice recovery per cent and physico-chemical traits viz; aroma, grain length and breadth before and after cooking, grain length and breadth ratio, kernel elongation ratio, water uptake ratio, volume expansion ratio and gelatinization temperature. Analysis of variance indicated significant difference (p<0.05 among genotypes exhibiting wealth of variability. No heterosis for hulling and milling percentage, kernel length and length breadth ratio was observed. Hybrids were characterized as intermediate between the parents for grain quality and physico-chemical traits. Therefore both the parents need to possess aroma, long slender grains with intermediate gelatinization temperature ( GT to develop aromatic, long grain basmati hybrids. The restorers Basmati 385 was characterized as good general combiner for all grain quality and physico-chemical traits while Karnal Local for grain quality and HKR 241 for physico-chemical attributes. These restorers in combination with basmati CMS lines could be utilized for developing basmati hybrids. Heterotic hybrids for grain yield IR 58025A x Basmati 385 and IR 58025A x Karnal Local with significant SCA effects were identified as specific combinations for grain quality and physico-chemical traits

  15. 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.

  16. 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...

  17. Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells

    DEFF Research Database (Denmark)

    Ali; Hamam; Alfayez;

    2016-01-01

    The epigenetic mechanisms promoting lineage-specific commitment of human skeletal (mesenchymal or stromal) stem cells (hMSCs) into adipocytes or osteoblasts are still not fully understood. Herein, we performed an epigenetic library functional screen and identified several novel compounds, including...... abexinostat, which promoted adipocytic and osteoblastic differentiation of hMSCs. Using gene expression microarrays, chromatin immunoprecipitation for H3K9Ac combined with high-throughput DNA sequencing (ChIP-seq), and bioinformatics, we identified several key genes involved in regulating stem cell...... or stromal) stem cells (hMSCs). These data provide new insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways controlling adipocyte and osteoblast differentiation of hMSCs. Manipulating...

  18. The P2 promoter of the IGF1 gene is a major epigenetic locus for GH responsiveness.

    Science.gov (United States)

    Ouni, M; Belot, M P; Castell, A L; Fradin, D; Bougnères, P

    2016-02-01

    Short children using growth hormone (GH) to accelerate their growth respond to this treatment with a variable efficacy. The causes of this individual variability are multifactorial and could involve epigenetics. Quantifying the impact of epigenetic variation on response to treatments is an emerging challenge. Here we show that methylation of a cluster of CGs located within the P2 promoter of the insulin-like growth factor 1 (IGF1) gene, notably CG-137, is inversely closely correlated with the response of growth and circulating IGF1 to GH administration. For example, variability in CG-137 methylation contributes 25% to variance of growth response to GH. Methylation of CGs in the P2 promoter is negatively associated with the increased transcriptional activity of P2 promoter in patients' mononuclear blood cells following GH administration. Our observation indicates that epigenetics is a major determinant of GH signaling (physiology) and of individual responsiveness to GH treatment (pharmacoepigenetics). PMID:25869012

  19. 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

  20. 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.