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Medically assisted reproduction, now considered a routine, successful treatment for infertility worldwide, has produced at least 8 million live births. However, a growing body of evidence is pointing toward an increased incidence of epigenetic/imprinting disorders in the offspring, raising concern that the techniques involved may have an impact on crucial stages of early embryo and fetal development highly vulnerable to epigenetic influence. In this paper, the key role of methylation processes in epigenesis, namely the essential biochemical/metabolic pathways involving folates and one-carbon cycles necessary for correct DNA/histone methylation, is discussed. Furthermore, potential contributors to epigenetics dysregulation during the three phases of assisted reproduction: preparation for and controlled ovarian hyperstimulation (COH); methylation processes during the preimplantation embryo culture stages; the effects of unmetabolized folic acid (UMFA) during embryogenesis on imprinting methyl "tags", are described. Advances in technology have opened a window into developmental processes that were previously inaccessible to research: it is now clear that ART procedures have the potential to influence DNA methylation in embryonic and fetal life, with an impact on health and disease risk in future generations. Critical re-evaluation of protocols and procedures is now an urgent priority, with a focus on interventions targeted toward improving ART procedures, with special attention to in vitro culture protocols and the effects of excessive folic acid intake. [ABSTRACT FROM AUTHOR]

The article focuses on the history of epigenetics through a multicenter approach. Topics discussed include the similarities between genetics and embryology during the early 20th century; American embryologist and geneticist Thomas Hunt Morgan's works on the chromosome theory of heredity; and research on the role of gene expression in embryonic development and cell differentiation.

Objectives: To determine whether epigenetic markers predict dimensional ratings of depression in maltreated children. Method: A genome-wide methylation study was completed using the Illumina 450K BeadChip array in 94 maltreated and 96 healthy nontraumatized children with saliva-derived DNA. The 450K BeadChip does not include any methylation sites in the exact location as sites in candidate genes previously examined in the literature, so a test for replication of prior research findings was not feasible. Results: Methylation in 3 genes emerged as genome-wide-significant predictors of depression: DNA-Binding Protein Inhibitor ID-3 (IDS); Glutamate Receptor, Ionotropic N-methyl-D-aspartate (NMDA) 1 (GR1N1); and Tubulin Polymerization Promoting Protein (TPPP) [p < 5.0 x 10-7, all analyses). These genes are all biologically relevant with ID3 involved in the stress response, GRIN1 involved in neural plasticity, and TPPP involved in neural circuitry development. Methylation in CpG sites in candidate genes were not predictors of depression at significance levels corrected for whole genome testing, but maltreated and control children did have significantly different β values after Bonferroni correction at multiple methylation sites in these candidate genes (e.g., BDNF, NR3C1, FKBP5). Conclusions: This study suggests that epigenetic changes in ID3, GRIN1, and TPPP genes, in combination with experiences of maltreatment, may confer risk for depression in children. The study adds to a growing body of literature supporting a role for epigenetic mechanisms in the pathophysiology of stress-related psychiatric disorders. Although epigenetic changes are frequently long lasting, they are not necessarily permanent. Consequently, interventions to reverse the negative biological and behavioral sequelae associated with child maltreatment are briefly discussed. [ABSTRACT FROM AUTHOR]

Highlights: [•] Epigenetics explains how environment or early-life events have lasting outcomes on overall health. [•] Sexual differentiation of neuroendocrine systems is a useful neuroepigenetic model. [•] Neuroepigenetic alterations may be stable or plastic across a lifespan. [ABSTRACT FROM AUTHOR]

Abstract: Epigenetic events controlling the transcriptional regulation of genes involved in endometrial function during the estrous cycle and early pregnancy have only sparsely been investigated. We analyzed the gene expression of DNA methyltransferases and the most prominent endocrine transcriptional mediator estrogen receptor alpha (ESR1) in the bovine endometrium of heifers at 0, 12 and 18days following estrous and at day 18 after insemination. The luminometric methylation assay for the investigation of global DNA methylation and an elegant combination of methylation-sensitive high resolution melting and pyrosequencing for local methylation levels of ESR1 were deployed. In spite of differential gene expression of ESR1 among groups, no differences in endometrial ESR1 DNA methylation during neither estrous cycle nor early pregnancy were determined. Global DNA methylation prevailed at similar low levels in endometrium, likely controlled by the observed moderate DNMT3b expression. Thus, the epigenetic contribution of DNA methylation influencing endometrial function seems rather limited. However, because a control tissue expressing only minute amounts of ESR1 transcripts was locally significantly higher methylated, DNA methylation might contribute to an appropriate tissue-specific expression status underlying further specific control mechanisms of gene transcription. [Copyright &y& Elsevier]

Purpose: Ionizing radiation induces cellular damage through both direct and indirect mechanisms, which may include effects from epigenetic changes. The purpose of this study was to determine the effect of ionizing radiation on DNA methylation patterns that may be associated with altered gene expression. Materials and methods: Sixteen human tumor cell lines originating from various cancers were initially tested for radiation sensitivity by irradiating them with γ-radiation in vitro and subsequently, radiation sensitive and resistant cell lines were treated with different doses of a demethylating agent, 5-Aza-2′-Deoxycytidine (5-aza-dC) and a chromatin modifier, Trichostatin-A (TSA). Survival of these cell lines was measured using 3-(4, 5-Dimethylthiazol- 2-yl)-2, 5-diphenyltetrazolium (MTT) and clonogenic assays. The effect of radiation on global DNA methylation was measured using reverse phase high performance liquid chromatography (RP-HPLC). The transcription response of methylated gene promoters, from cyclin-dependent kinase inhibitor 2A (p16INK4a) and ataxia telangiectasia mutated (ATM) genes, to radiation was measured using a luciferase reporter assay. Results: γ-radiation resistant (SiHa and MDAMB453) and sensitive (SaOS2 and WM115) tumor cell lines were examined for the relationship between radiation sensitivity and DNA methylation. Treatment of cells with 5-aza-dC and TSA prior to irradiation enhanced DNA strand breaks, G2/M phase arrest, apoptosis and cell death. Exposure to γ-radiation led to global demethylation in a time-dependent manner in tumor cells in relation to resistance and sensitivity to radiation with concomitant activation of p16INK4a and ATM gene promoters. Conclusion: These results provide important information on alterations in DNA methylation as one of the determinants of radiation effects, which may be associated with altered gene expression. Our results may help in delineating the mechanisms of radiation resistance in tumor cells, which can influence diagnosis, prognosis and eventually therapy for human cancers. [ABSTRACT FROM AUTHOR]

Originally, the finding of a particular distribution of cytidine-guanosine dinucleotides (CpGs) in genomic DNA was considered to be an interesting structural feature of eukaryotic genome organization. Despite a global depletion of CpGs, genes are frequently associated with CpG clusters called CpG islands (CGIs). CGIs are prevalently unmethylated but often found methylated in pathologic situations. On the other hand, CpGs outside of CGIs are generally methylated and are found mainly in the heterochromatic fraction of the genome. Hypomethylation of those CpGs is associated with genomic instability in malignancy. Additionally, CpG-rich and CpG-poor regions, as well as CpG-shores, are defined. Usually, the methylation status inversely correlates with gene expression. Methylation of CpGs, as well as demethylation and generation of hydroxmethyl-cytosines, is strictly regulated during development and differentiation. This review deals with the relevance of the organizational features of CpGs and their relation to each other. [ABSTRACT FROM AUTHOR]

Abstract: Cardiovascular complications are a chief cause of mortality and morbidity in diabetic patients. Recent studies suggest that epigenetic changes which may arise as a consequence of environmental factors play an important role in predisposition to disease. Epigenetic mechanisms such as DNA methylation, chromatin remodeling and histone modifications regulate the gene expression in response to environmental signals. Role of epigenetics has been recognized in the pathology of diabetes, however its role in diabetic associated cardiomyopathy remains largely unexplored. In this article, we review current literature on the epigenetic mechanisms involved in diabetes and discuss recent evidence of epigenetic changes that may play an important role in pathophysiology of DCM. [Copyright &y& Elsevier]

Abstract: Formaldehyde (FA), a volatile organic compound, is a ubiquitous air pollutant that is classified as ‘Carcinogenic to humans (Group 1)’ by . As a well-recognized human carcinogen, its carcinogenic mechanisms are still poorly understood. Previous studies have emphasized on genetic changes. However, little is known about the epigenetic mechanisms of FA exposure. In this study, We not only characterized the epigenomic response to long-term low-dose FA exposure in 16HBE cells, but also examined the expression of DNA methyltransferases (DNMTs) and the methyl-CpG-binding protein DNA-binding domain protein 2 (MBD2). Each week the 16HBE cells were treated with 10μM FA for 24h (h). After 24 weeks (W) of exposure to FA, the level of genomic DNA methylation gradually decreased in a time-related manner. Moreover, our results showed that FA exposure down-regulated the expression of DNMT3a and DNMT3b at both mRNA and protein level, and up-regulated the levels of DNMT1 and MBD2 at both mRNA and protein level. Our study indicated that long-term FA exposure could disrupt genomic DNA methylation, which may be one of the possible underlying carcinogenic mechanisms of FA. [Copyright &y& Elsevier]

Abstract: Aberrant DNA methylation is induced at specific promoter CpG islands (CGIs) in contrast with mutations. The specificity is influenced by genome architecture and epigenetic factors, but their relationship is still unknown. In this study, we isolated promoter CGIs susceptible and resistant to aberrant methylation induction during prostate and breast carcinogenesis. The effect of genome architecture was more evident for promoter CGIs susceptible in both of the two tissues than for promoter CGIs susceptible only in one tissue. Multivariate analysis of promoter CGIs with tissue-nonspecific susceptibility showed that genome architecture, namely a remote location from SINE (OR=5.98; 95% CI=2.33–15.34) and from LINE (OR=2.08; 95% CI=1.03–4.21), was associated with increased susceptibility, independent of epigenetic factors such as the presence of RNA polymerase II (OR=0.09; 95% CI=0.02–0.48) and H3K27me3 (OR=3.28; 95% CI=1.17–9.21). These results showed that methylation susceptibility of promoter CGIs is determined both by genome architecture and epigenetic factors, independently. [Copyright &y& Elsevier]

Abstract: Histone modifications play an important role in the formation of an epigenetic memory system that maintains cellular identity. Their complex patterns have been suggested to constitute a histone code, which encodes for specific forms of chromatin. According to the histone code hypothesis these specific patterns are passed on from one cell generation to the next. This enables cells to keep a specific gene expression pattern even in absence of the specific transcription factors that initiated the expression of lineage determining genes. The methylation of specific lysine residues within the histone tails plays a particularly important role in defining the histone modification pattern as mutations of the enzymes that catalyze the formation or the removal of methyl groups have severe effects on cellular physiology. Lysines can get mono-, di- or trimethylated, but the molecular function of the different modification states is still not fully understood. In the following review we will highlight recent data that try to tackle this question and discuss their potential impact for our understanding of the role of histone methylation in epigenetic inheritance. [Copyright &y& Elsevier]

Abstract: Developmental plasticity can be defined as the ability of one genotype to produce a range of phenotypes in response to environmental conditions. Such plasticity can be manifest at the level of individual cells, an organ, or a whole organism. Imprinted genes are a group of approximately 100 genes with functionally monoallelic, parental-origin specific expression. As imprinted genes are critical for prenatal growth and metabolic axis development and function, modulation of imprinted gene dosage has been proposed to play a key role in the plastic development of the unborn foetus in response to environmental conditions. Evidence is accumulating that imprinted dosage may also be involved in controlling the plastic potential of individual cells or stem cell populations. Imprinted gene dosage can be modulated through canonical, transcription factor mediated mechanisms, or through the relaxation of imprinting itself, reactivating the normally silent allele. [Copyright &y& Elsevier]

Abstract: Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the inhibitors are either previously reported inhibitors of related enzymes or compounds derived from these. Development in terms of selectivity and potency is still pertinent. Several reports on the development of functional assays have been published. [Copyright &y& Elsevier]

Abstract: DNA methylation provides a plausible link between the environment and alterations in gene expression that may lead to disease phenotypes. Lead exposure can change DNA methylation status. Here, we hypothesized that the methylation of the ALAD gene promoter may play an important role in lead toxicity. To determine whether the methylation level of the ALAD promoter is associated with the risk of lead poisoning, we conducted a case–control study of 103 workers from a battery plant and 103 healthy volunteers with matching age and gender distribution. We employed real-time PCR and methylation-specific PCR (MSP) in cell models to determine the relationship between ALAD methylation level and transcription level. We found lead exposure to increase the ALAD gene methylation level and down-regulate ALAD transcription. The difference in methylation frequencies between exposures and controls was statistically significant (p =0.002), and individuals with methylated ALAD gene showed an increased risk of lead poisoning (adjusted OR=3.57, 95% CI, 1.55–8.18). This study suggests that the lead-exposure-induced increases in ALAD methylation may be involved in the mechanism of lead toxicity. [Copyright &y& Elsevier]

The aberrant epigenetic landscape of a cancer cell is characterized by global genomic hypomethylation, CpG island promoter hypermethylation of tumor suppressor genes, and changes in histone modification patterns, as well as altered expression profiles of chromatin-modifying enzymes. Recent advances in the field of epigenetics have revealed that microRNAs' expression is also under epigenetic regulation and that certain microRNAs control elements of the epigenetic machinery. The reversibility of epigenetic marks catalyzed the development of epigenetic-altering drugs. However, a better understanding of the intertwined relationship between genetics, epigenetics and microRNAs is necessary in order to resolve how gene expression aberrations that contribute to tumorigenesis can be therapeutically corrected. [ABSTRACT FROM AUTHOR]

Sponsored by the New York Academy of Sciences, the Warren Alpert Medical School of Brown University and the University of Massachusetts Boston, 'Behavioral Epigenetics' was held on October 29-30, 2010 at the University of Massachusetts Boston Campus Center, Boston, Massachusetts. This meeting featured speakers and panel discussions exploring the emerging field of behavioral epigenetics, from basic biochemical and cellular mechanisms to the epigenetic modulation of normative development, developmental disorders, and psychopathology. This report provides an overview of the research presented by leading scientists and lively discussion about the future of investigation at the behavioral epigenetic level. [ABSTRACT FROM AUTHOR]

Abstract: Alcohol exposure during pregnancy induces a range of disorders in the offspring. Methylation changes in imprinted genes may play a role in the teratogenic effects of alcohol. We evaluated the possible effects of alcohol administration in pregnant mice on the methylation pattern of 5 imprinted genes (H19, Gtl2, Peg1, Snrpn and Peg3) in somatic and sperm cell DNAs of the male offspring. The effects observed were a 3% (p <0.005) decrease in the number of methylated CpGs of H19 in the F1 offspring sperm, a 4% (p <0.005) decrease in the number of methylated CpGs of H19 in the F2 offspring brain and a 26% (p <0.05) decrease in the mean sperm concentration. CpGs 1 and 2 of the H19 CTCF-binding site 2 exhibited significant methylation percentage losses. H19 CTCF-binding sites are important for the regulation of Igf2 gene expression. The hypomethylation of H19 may contribute to the decreased spermatogenesis in the offspring. [Copyright &y& Elsevier]

Abstract: Epigenetic modifications characterized by DNA methylation, histone modifications, and chromatin remodeling are important regulators in a number of biological processes, including spermatogenesis. Several genes in the testes are regulated through epigenetic mechanisms, indicating a direct influence of epigenetic mechanisms on the process of spermatogenesis. In the present article, we have provided a comprehensive review of the epigenetic processes in the testes, correlation of epigenetic aberrations with male infertility, impact of environmental factors on the epigenome and male fertility, and significance of epigenetic changes/aberrations in assisted reproduction. The literature review suggested a significant impact of epigenetic aberrations (epimutations) on spermatogenesis, and this could lead to male infertility. Epimutations (often hypermethylation) in several genes, namely MTHFR, PAX8, NTF3, SFN, HRAS, JHM2DA, IGF2, H19, RASGRF1, GTL2, PLAG1, D1RAS3, MEST, KCNQ1, LIT1, and SNRPN, have been reported in association with poor semen parameters or male infertility. Environmental toxins/drugs may affect fertility via epigenetic modifications. For example, 5-aza-2′-deoxycytidine, an anticancer agent, causes a decrease in global DNA methylation that leads to altered sperm morphology, decreased sperm motility, decreased fertilization capacity, and decreased embryo survival. Similarly, Endocrine disruptors, such as methoxychlor (an estrogenic pesticide) and vinclozolin (an anti-androgenic fungicide) have been found by experiments on animals to affect epigenetic modifications that may cause spermatogenic defects in subsequent generations. Assisted reproduction procedures that have been considered rather safe, are now being implicated in inducing epigenetic changes that could affect fertility in subsequent generations. Techniques such as intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI) may increase the incidence of imprinting disorders and adversely affect embryonic development by using immature spermatozoa that may not have established proper imprints or global methylation. Epigenetic changes, in contrast to genetic aberrations, may be less deleterious because they are potentially reversible. Further research could identify certain drugs capable of reversing epigenetic changes. [Copyright &y& Elsevier]

Abstract: Epigenetic mechanisms maintain heritable changes in gene expression and chromatin organization over many cell generations. Importantly, deregulated epigenetic mechanisms play a key role in a wide range of human malignancies, including liver cancer. Hepatocellular carcinoma (HCC), which originates from the hepatocytes, is by far the most common liver cancer, with rates and aetiology that show considerable geographic variation. Various environmental agents and lifestyles known to be risk factors for HCC (such as infection by hepatitis B virus (HBV) and hepatitis C virus (HCV), chronic alcohol intake, and aflatoxins) are suspected to promote its development by eliciting epigenetic changes, however the precise gene targets and underlying mechanisms have not been elucidated. Many recent studies have exploited conceptual and technological advances in epigenetics and epigenomics to investigate the role of epigenetic events induced by environmental factors in HCC tumors and non-tumor precancerous (cirrhotic) lesions. These studies have identified a large number of genes and pathways that are targeted by epigenetic deregulation (changes in DNA methylation, histone modifications and RNA-mediated gene silencing) during the development and progression of HCC. Frequent identification of aberrant epigenetic changes in specific genes in cirrhotic tissue is consistent with the notion that epigenetic deregulation of selected genes in pre-malignant lesions precedes and promotes the development of HCC. In addition, several lines of evidence argue that some environmental factors (such as HBV virus) may abrogate cellular defense systems, induce silencing of host genes and promote HCC development via an “epigenetic strategy”. Finally, profiling studies reveal that HCC tumors and pre-cancerous lesions may exhibit epigenetic signatures associated with specific risk factors and tumor progression stage. Together, recent evidence underscores the importance of aberrant epigenetic events induced by environmental factors in liver cancer and highlights potential targets for biomarker discovery and future preventive and therapeutic strategies. [Copyright &y& Elsevier]

Abstract: The analysis of genomic alterations in acute lymphoblastic leukemia (ALL) has provided new insights for prognosis and possible targets of novel therapies. In T-ALL the role of molecular abnormalities has still to be determined. Deregulated promoter hypermethylation of critical genes like PAX5 may have a significant impact on the course of ALL. Samples derived from 75 patients with ALL (B-ALL=24, T-ALL=51) and from healthy volunteers were analyzed. PAX5 expression was assessed by micro-array analysis (HG-U133plus 2.0) and correlated with promoter CpG island methylation of PAX5 using a pyrosequencing approach. The analyzed CpG marks in the promoter region of PAX5 were completely and uniformly unmethylated in the control group of healthy individuals. The T-ALL cases featured even higher methylation levels (median: 20%) with a strong variation of values of up to 85% methylation. Analysis of the association of altered methylation levels with gene expression data indicated a differential epigenetic regulation of PAX5 through promoter methylation which may contribute to the pathogenesis of this disease. [Copyright &y& Elsevier]

Sexual differentiation of the brain is a crucial developmental process that enables the lifelong expression of sexually dimorphic behaviors, including those necessary for successful reproduction. During a perinatal sensitive period, gonadal hormones defeminize and masculinize the male brain, and a lack of gonadal steroids allows for feminization in the female. This hormonally-induced differentiation permanently alters neural structures, creating highly dimorphic brain regions; however, the mechanism by which hormones exert their long-lasting effects are still largely unknown. Epigenetic processes such as DNA methylation and histone modifications serve as an interface for environmental stimuli to exert control over the genome. These modifications have the capacity to activate or repress gene expression, thereby shaping the developmental outcomes of cells, circuits, and structures in the brain. Sex differences in methylation, methyl-binding proteins, and chromatin modifications indicate that epigenetic mechanism may be important for sexual differentiation of the brain. The data outlined in this review provide evidence that gonadal hormones in the neonatal brain influence epigenetic processes such as DNA methylation and histone acetylation, but also emphasize the primitive status of our current understanding of epigenetics and sexual differentiation and the brain. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Addiction is a debilitating psychiatric disorder, with a complex aetiology involving the interaction of inherited predispositions and environmental factors. Emerging evidence suggests that epigenetic alterations to the genome, including DNA methylation and histone modifications, are important mechanisms underlying addiction and the neurobiological response to addictive substances. In this review, we introduce the reader to epigenetic mechanisms and describe a potential role for dynamic epigenetic changes in mediating addictive behaviours via long-lasting changes in gene expression. We summarize recent findings from both molecular and behavioural experiments elucidating the role of epigenetic changes in mediating the addictive potential of various drugs of abuse, including cocaine, amphetamine and alcohol. The implications of these findings for molecular studies of addiction and the future development of novel therapeutic interventions are also discussed. [ABSTRACT FROM AUTHOR]

Abstract: Epigenetics, the nongenetic component of how chromatin structure influences gene expression, is amazingly complex, and linking how environmental stimuli can influence epigenetic ‘gene programs’ in specific nerve cells to ultimately control behavior is a seemingly insurmountable puzzle. Cocaine is a highly potent stimulus capable of influencing behavior for the lifetime of an organism. Not surprisingly, psychostimulant-induced epigenetic regulation of gene expression has thus been identified as key to understanding the pathology of addiction. In addition to identifying this essential role of epigenetics in addiction, several important concepts have emerged such as the importance of global, temporal, and spatial control of mRNA expression in considering any given histone modification''s influence on a given gene. Adding to this complexity, one has to account for the cumulative influence of other epigenetic modifications on a gene''s transcription in addition to the interplay between transcription factors and chromatin structure. This review highlights how bioinformatic, molecular, and behavioral studies on addiction provide new insight into these concepts and outlines two distinct psychostimulant-induced patterns of chromatin regulation which are thought to underlie unique programs of gene expression that contribute importantly to the addicted state. [Copyright &y& Elsevier]

Abstract: Epigenetic chromatin remodeling, including reversible histone methylation, regulates gene transcription in brain development and synaptic plasticity. Aberrant chromatin modifications due to mutant chromatin enzymes or chemical exposures have been associated with neurological or psychiatric disorders such as mental retardation, schizophrenia, depression, and drug addiction. Some chromatin enzymes, such as histone demethylases JARID1C and UTX, are coded by X-linked genes which are not X-inactivated in females. The higher expression of JARID1C and UTX in females could contribute to sex differences in brain development and behavior. [Copyright &y& Elsevier]

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 messenger RNA (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 hypothesise that epigenetics may be the missing link in understanding the mechanism behind RIGI. [ABSTRACT FROM AUTHOR]

Background: Derangements in the maternal methylation pathway, expressed by global hypomethylation and hyperhomocysteinemia, are associated with the risk of having a child with a congenital heart defect (CHD). It is not known whether periconception exposure to these metabolic derangements contributes to chromosome segregation and metabolic programming of this pathway in the foetus. Design: In a Dutch population-based case–control study of 143 children with CHD and 186 healthy children, we investigated S- adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), total homocysteine (tHcy), the vitamins folate and B12 and the functional single nucleotide polymorphisms in the folate gene MTHFR 677C>T and 1298A>C. Comparisons were made between cases and controls adjusting for age, medication, vitamin use and CHD family history. Results: In the overall CHD group, the median concentrations of SAM (P = 0Æ011), folate in serum (P = 0Æ021) and RBC (P = 0Æ030) were significantly higher than in the controls. Subgroup analysis showed that this was mainly attributable to complex CHD with higher SAM (P < 0Æ001), SAH (P = 0 Æ012) and serum folate (P = 0Æ010) independent of carriership of MTHFR polymorphisms. Highest concentrations of SAM, SAH and folate RBC were observed in complex syndromic CHD. The subgroup of children with Down syndrome, however, showed significantly higher SAH (P = 0Æ037) and significantly lower SAM:SAH ratio (P = 0Æ034) compared with other complex CHD, suggesting a state of global hypomethylation. Conclusion:High concentrations of methylation biomarkers in very young children are associated with complex CHD. Down syndrome and CHD may be associated with a global hypomethylation status, which has to be confirmed in tissues and global DNA methylation in future studies. [ABSTRACT FROM AUTHOR]

As potential regulators of DNA accessibility and activity, epigenetic modifications offer a mechanism by which the environment can moderate the effects of genes. To date, however, there have been relatively few studies assessing epigenetic modifications associated with post-traumatic stress disorder (PTSD). Here we investigate PTSD-associated methylation differences in 33 genes previously shown to differ in whole blood-derived gene expression levels between those with vs. without the disorder. Drawing on DNA samples similarly obtained from whole blood in 100 individuals, 23 with and 77 without lifetime PTSD, we used methylation microarray data to assess whether these 33 candidate genes showed epigenetic signatures indicative of increased risk for, or resilience to, PTSD. Logistic regression analyses were performed to assess the main and interacting effects of candidate genes' methylation values and number of potentially traumatic events (PTEs), adjusting for age and other covariates. Results revealed that only one candidate gene - MAN2C1} - showed a significant methylation x PTE interaction, such that those with both higher MAN2C1 methylation and greater exposure to PTEs showed a marked increase in risk of lifetime PTSD (OR 4.35, 95% CI: 1.07, 17.77, p=0.04). These results indicate that MAN2C1 methylation levels modify cumulative traumatic burden on risk of PTSD, and suggest that both gene expression and epigenetic changes at specific loci are associated with this disorder. [ABSTRACT FROM AUTHOR]

Abstract: The genetic changes leading to the development of human cancer are accompanied by alterations in the structure and modification status of chromatin, which represent powerful regulatory mechanisms for gene expression and genome stability. These epigenetic alterations have sparked interest into deciphering the regulatory pathways and function of post-translational modifications of histones during the initiation and progression of cancer. In this review we describe and summarize the current knowledge of several histone lysine methyltransferase and demethylase pathways relevant to cancer. Mechanistic insight into histone modifications will pave the way for the development and therapeutic application of “epidrugs” in cancer. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Numerous epigenetic modifications have been identified and correlated with transcriptionally active euchromatin or repressed heterochromatin and many enzymes responsible for the addition and removal of these marks have been characterized. However, less is known regarding how these enzymes are regulated and targeted to appropriate genomic locations. Mammalian CXXC finger protein 1 is an epigenetic regulator that was originally identified as a protein that binds specifically to any DNA sequence containing an unmethylated CpG dinucleotide. Mouse embryos lacking CXXC finger protein 1 die prior to gastrulation, and embryonic stem cells lacking CXXC finger protein 1 are viable but are unable to achieve cellular differentiation and lineage commitment. CXXC finger protein 1 is a regulator of both cytosine and histone methylation. It physically interacts with DNA methyltransferase 1 and facilitates maintenance cytosine methylation. Rescue studies reveal that CXXC finger protein 1 contains redundant functional domains that are sufficient to support cellular differentiation and proper levels of cytosine methylation. CXXC finger protein 1 is also a component of the Setd1 histone H3-Lys4 methyltransferase complexes and functions to target these enzymes to unmethylated CpG islands. Depletion of CXXC finger protein 1 leads to loss of histone H3-Lys4 tri-methylation at CpG islands and inappropriate drifting of this euchromatin mark into areas of hetero-chromatin. Thus, one function of CXXC finger protein 1 is to serve as an effector protein that interprets cytosine methylation patterns and facilitates crosstalk with histone-modifying enzymes. [ABSTRACT FROM AUTHOR]

Epigenetics comprises various mechanisms that mold chromatin structures and regulate gene expression with stability, thus defining cell identity and function and adapting cells to environmental changes. Alteration of these mechanisms contributes to the inception of various pathological conditions. Given the complexity of the immune system, one would predict that a higher-order, supragenetic regulation is indispensable for generation of its constituents and control of its functions. Here, we summarize various aspects of immune system physiology and pathology in which epigenetic pathways have been implicated. Increasing knowledge in this field, together with the development of specific tools with which to manipulate epigenetic pathways, might form a basis for new strategies of immune function modulation, both to optimize immune therapies for infections or cancer and to control immune alterations in aging or autoimmunity. [ABSTRACT FROM AUTHOR]

Abstract: DNA methylation is a gene-silencing and host defense system that can down-regulate viral gene expression in mammalian cells. An established targeted DNA methylation method was used to demonstrate that genome-integrated CMV and adenovirus type 5 E1A promoters were hypermethylated after MCF7 and HEK293 cells were transfected with in vitro methylated viral promoter fragments. In both cases, the targeted methylation-induced gene silencing could be reversed by addition of 5-aza-2′-deoxycytidine, confirming that the CMV and E1A promoters are regulated by DNA methylation. The kinetics of the targeted DNA methylation was determined using a reporter system in live cells. In conclusion, targeted DNA methylation is able to efficiently silence susceptible viral promoters and provides an alternative strategy to study the impact of loci-specific DNA methylation in viral gene expression. [Copyright &y& Elsevier]

Abstract: DNA methylation plays a vital role in normal cellular function, with aberrant methylation signatures being implicated in a growing number of human pathologies and complex human traits. Methods based on the modification of genomic DNA with sodium bisulfite are considered the ‘gold-standard’ for DNA methylation profiling on genomic DNA; however they require large amounts of DNA and may be prohibitively expensive when used on the large sample sizes necessary to detect small effects. DNA pooling approaches are already widely used in large-scale studies of DNA sequence and gene expression. In this paper, we describe the application of this economical DNA pooling technique to the study of DNA methylation profiles. This method generates accurate quantitative assessments of group DNA methylation averages, reducing the time, cost and amount of DNA starting material required for large-scale epigenetic investigation of disease phenotypes. [ABSTRACT FROM AUTHOR]

Abstract: Substantial evidence indicates that exposure to bisphenol A (BPA) during early development may increase breast cancer risk later in life. The changes may persist into puberty and adulthood, suggesting an epigenetic process being imposed in differentiated breast epithelial cells. The molecular mechanisms by which early memory of BPA exposure is imprinted in breast progenitor cells and then passed onto their epithelial progeny are not well understood. The aim of this study was to examine epigenetic changes in breast epithelial cells treated with low-dose BPA. We also investigated the effect of BPA on the ERα signaling pathway and global gene expression profiles. Compared to control cells, nuclear internalization of ERα was observed in epithelial cells preexposed to BPA. We identified 170 genes with similar expression changes in response to BPA. Functional analysis confirms that gene suppression was mediated in part through an ERα-dependent pathway. As a result of exposure to BPA or other estrogen-like chemicals, the expression of lysosomal-associated membrane protein 3 (LAMP3) became epigenetically silenced in breast epithelial cells. Furthermore, increased DNA methylation in the LAMP3 CpG island was this repressive mark preferentially occurred in ERα-positive breast tumors. These results suggest that the in vitro system developed in our laboratory is a valuable tool for exposure studies of BPA and other xenoestrogens in human cells. Individual and geographical differences may contribute to altered patterns of gene expression and DNA methylation in susceptible loci. Combination of our exposure model with epigenetic analysis and other biochemical assays can give insight into the heritable effect of low-dose BPA in human cells. [ABSTRACT FROM AUTHOR]

Background: Successful gametogenesis requires the establishment of an appropriate epigenetic state in developing germ cells. Nevertheless, an association between abnormal spermatogenesis and epigenetic disturbances in germline-specific genes remains to be demonstrated.Methods: In this study, the DNA methylation pattern of the promoter CpG island (CGI) of two germline regulator genes--DAZL and DAZ, was characterized by bisulphite genomic sequencing in quality-fractioned ejaculated sperm populations from normozoospermic (NZ) and oligoasthenoteratozoospermic (OAT) men.Results: OAT patients display increased methylation defects in the DAZL promoter CGI when compared with NZ controls. Such differences are recorded when analyzing sperm fractions enriched either in normal or defective germ cells (P< 0.001 in both cases). Significant differences in DNA methylation profiles are also observable when comparing the qualitatively distinct germ cell fractions inside the NZ and OAT groups (P= 0.003 and P= 0.007, respectively). Contrastingly, the unmethylation pattern of the DAZ promoter CGI remains correctly established in all experimental groups.Conclusions: An association between disrupted DNA methylation of a key spermatogenesis gene and abnormal human sperm is described here for the first time. These results suggest that incorrect epigenetic marks in germline genes may be correlated with male gametogenic defects. [ABSTRACT FROM AUTHOR]

Abstract: Abdominal aortic aneurysm (AAA) is a common disease associated with significant cardiovascular morbidity and mortality. The pathogenesis of AAA is poorly defined, making targeting of new therapies problematic. Current evidence favours an interaction of multiple environmental and genetic factors in the initiation and progression of AAA. Epigenetics is the term used to define the properties of the genome that are not explained by the primary sequence, but are due to the modifications of DNA and/or associated proteins. Previous research indicates the association of gene specific promoter DNA hyper-methylation and global DNA hypo-methylation with atherosclerosis. Evidence also suggests an important role for epigenetic processes such as histone acetylation in cardiovascular diseases including atherosclerosis and restenosis. Altered DNA methylation or histone acetylation occur in inflammation, cellular proliferation and remodelling processes and therefore maybe relevant to the pathology of AAA. Important risk factors for AAA, including cigarette smoking, older age, male gender and hypertension, have been linked with epigenetic effects and thus could act in this way to promote AAA. In this review, we discuss the potential role of epigenetic mechanisms in AAA. Since epigenetic alterations are to some extent reversible, further study of this area may identify new treatment targets for AAA. [ABSTRACT FROM AUTHOR]

Abstract: Epigenetics describes the study of stable, reversible alterations to the genome that affect gene expression and genome function, the most studied mechanisms are DNA methylation and histone modifications. Over recent years there has been rapid progress to elucidate the nature and role of the mechanisms involved in promoter hypermethylation during carcinogenesis, however, the mechanism behind one of the earliest epigenetic observations in cancer, genome-wide hypomethylation, remains unclear. Current evidence is divided between the hypotheses that hypomethylation is either an important early cancer-causing aberration or that it is a passive inconsequential side effect of carcinogenesis. With recent discoveries of gene–body methylation, fast cyclic methylation of hormone dependent genes and candidate proteins involved in DNA demethylation elucidation of the role of hypomethylation and the mechanism behind it appears ever closer. With the burgeoning use of DNA methyltransferase inhibitors as a cancer therapy there is an increased need to understand the mechanisms and importance of genome-wide hypomethylation in cancer. This review will discuss the timing and potential causes of genomic hypomethylation during carcinogenesis and will propose a way forward to understand the underlying mechanisms. [Copyright &y& Elsevier]

The biosynthesis and signaling of plant hormones play a critical role in almost all biological processes. It is well-documented that phytohormones cross-talk with each other. Epigenetic mechanisms were suggested to regulate expression of downstream targets in hormone signaling pathways that help implement hormone functions. This new layer of complexities that integrate epigenetic information such as DNA methylation, chromatin remodeling, histone modification, microRNAs and siRNAs with plant hormone signaling and regulations of gene expression, has been gradually revealed. In this short review, the author tries to assemble recent progress to establish a molecular linkage between these two large and momentum research fields and also to help readers digest the literature. [ABSTRACT FROM AUTHOR]

Epigenetics investigates heritable changes in gene expression that occur without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation and histone modifications, can change genome function under exogenous influence. We review current evidence indicating that epigenetic alterations mediate effects caused by exposure to environmental toxicants. Results obtained from animal models indicate that in utero or early-life environmental exposures produce effects that can be inherited transgenerationally and are accompanied by epigenetic alterations. The search for human equivalents of the epigenetic mechanisms identified in animal models is under way. Recent investigations have identified a number of environmental toxicants that cause altered methylation of human repetitive elements or genes. Some exposures can alter epigenetic states and the same and/or similar epigenetic alterations can be found in patients with the disease of concern. On the basis of current evidence, we propose possible models for the interplay between environmental exposures and the human epigenome. Several investigations have examined the relationship between exposure to environmental chemicals and epigenetics, and have identified toxicants that modify epigenetic states. Whether environmental exposures have transgenerational epigenetic effects in humans remains to be elucidated. In spite of the current limitations, available evidence supports the concept that epigenetics holds substantial potential for furthering our understanding of the molecular mechanisms of environmental toxicants, as well as for predicting health-related risks due to conditions of environmental exposure and individual susceptibility. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms contribute to the establishment and maintenance of cell-type-specific gene expression patterns. In this review, we focus on the functions of histone lysine methylation in the context of epigenetic gene regulation during developmental transitions. Over the past few years, analysis of histone lysine methylation in active and repressive nuclear compartments and, more recently, genome-wide profiling of histone lysine methylation in different cell types have revealed correlations between particular modifications and the transcriptional status of genes. Identification of histone methyltransferases (HMTases) and specific binding factors for most methylated lysine positions has provided a novel insight into the mechanisms of epigenetic gene regulation. In addition, analyses of HMTase knockout mice show that histone lysine methylation has important functions for normal development. In this study, we review mechanisms of gene activation and repression by histone lysine methylation and discuss them in the context of the developmental roles of HMTases. [ABSTRACT FROM AUTHOR]

Transcription, translation and subsequent protein modification represent the transfer of genetic information from the archival copy of DNA to the short-lived messenger RNA, usually with subsequent production of protein. Although all cells in an organism contain essentially the same DNA, cell types and functions differ because of qualitative and quantitative differences in their gene expression. Thus, control of gene expression is at the heart of differentiation and development. Epigenetic processes, including DNA methylation, histone modification and various RNA-mediated processes, are thought to influence gene expression chiefly at the level of transcription; however, other steps in the process (for example, translation) may also be regulated epigenetically. The following paper will outline the role epigenetics is believed to have in influencing gene expression. [ABSTRACT FROM AUTHOR]

Abstract: An organism''s behavioral and physiological and social milieu influence and are influenced by the epigenome, which is composed predominantly of chromatin and the covalent modification of DNA by methylation. Epigenetic patterns are sculpted during development to shape the diversity of gene expression programs in the organism. In contrast to the genetic sequence, which is determined by inheritance and is virtually identical in all tissues, the epigenetic pattern varies from cell type to cell type and is potentially dynamic throughout life. It is postulated here that different environmental exposures, including early parental care, could impact epigenetic patterns, with important implications for mental health in humans. Because epigenetic programming defines the state of expression of genes, epigenetic differences could have the same consequences as genetic polymorphisms. Yet in contrast to genetic sequence differences, epigenetic alterations are potentially reversible. This review will discuss basic epigenetic mechanisms and how epigenetic processes early in life might play a role in defining inter-individual trajectories of human behavior. In this regard, we will examine evidence for the possibility that epigenetic mechanisms can contribute to later-onset neurological dysfunction and disease. [Copyright &y& Elsevier]

The role of epigenetic phenomena in cancer biology is increasingly being recognized. Here we focus on the mechanisms and enzymes involved in regulating histone methylation and acetylation, and the modulation of histone variant expression and deposition. Implications of these epigenetic marks for tumor development, progression and invasiveness are discussed with a particular emphasis on breast cancer progression. [ABSTRACT FROM AUTHOR]

In this paper we describe a novel approach that may shed light on the genomic DNA methylation of organisms with non-resolved genomes. The LUminometric Methylation Assay (LUMA) is permissive for genomic DNA methylation studies of any genome as it relies on the use of methyl-sensitive and -insensitive restriction enzymes followed by polymerase extension via Pyrosequencing technology. Here, LUMA was used to characterize genomic DNA methylation in the lower brain stem region from 47 polar bears subsistence hunted in central East Greenland between 1999 and 2001. In these samples, average genomic DNA methylation was 57.9% ± 6.69 (SD; range was 42.0 to 72.4%). When genomic DNA methylation was related to brain mercury (Hg) exposure levels, an inverse association was seen between these two variables for the entire study population ( P for trend = 0.17). After dichotomizing animals by gender and controlling for age, a negative trend was seen amongst male animals ( P for trend = 0.07) but no associations were found in female bears. Such sexually dimorphic responses have been found in other toxicological studies. Our results show that genomic DNA methylation can be quantitatively studied in a highly reproducible manner in tissue samples from a wild organism with a non-resolved genome. As such, LUMA holds great promise as a novel method to explore consequential questions across the ecological sciences that may require an epigenetic understanding. [ABSTRACT FROM AUTHOR]

Abstract: The Ras-Association Domain Family (RASSF) comprises ten members, termed RASSF1 to RASSF10. RASSF1 to RASSF6 harbor a C-terminal Ras-association (RA) domain and RASSF7 to RASSF10 contain an N-terminal RA domain. Interestingly, it was observed that in various tumor types distinct RASSFs transcripts (e.g. RASSF1A and RASSF2A) are missing due to hypermethylation of their CpG island promoter. Since methylation of the RASSF1A promoter is described as an early and frequent event in tumorigenesis, RASSF1A could serve as a useful diagnostic marker in cancer screens. RASSFs are implicated in various cellular mechanisms including apoptosis, cell cycle control and microtubule stabilization, though little is known about the underlying mechanisms. Tumor suppressing functions were reported for several members. Here we review the current literature on RASSF members focusing on structural, functional and epigenetic aspects. Characterizing the cellular mechanisms that regulate the signaling pathways RASSFs are involved in, could lead to a deeper understanding of tumor development and, furthermore, to new strategies in cancer treatment. [Copyright &y& Elsevier]

The orchestrated expression of genes is essential for the development and survival of every organism. In addition to the role of transcription factors, the availability of genes for transcription is controlled by a series of proteins that regulate epigenetic chromatin remodeling. The two most studied epigenetic phenomena are DNA methylation and histone-tail modifications. Although a large body of literature implicates the deregulation of histone acetylation and DNA methylation with the pathogenesis of cancer, recently epigenetic mechanisms have also gained much attention in the neuroscientific community. In fact, a new field of research is rapidly emerging and there is now accumulating evidence that the molecular machinery that regulates histone acetylation and DNA methylation is intimately involved in synaptic plasticity and is essential for learning and memory. Importantly, dysfunction of epigenetic gene expression in the brain might be involved in neurodegenerative and psychiatric diseases. In particular, it was found that inhibition of histone deacetylases attenuates synaptic and neuronal loss in animal models for various neurodegenerative diseases and improves cognitive function. In this article, we will summarize recent data in the novel field of neuroepigenetics and discuss the question why epigenetic strategies are suitable therapeutic approaches for the treatment of brain diseases. [ABSTRACT FROM AUTHOR]

Chromatin states profoundly determine and maintain gene activity and gene repression in eukaryotic organisms. Regulation of chromatin involves chromatin remodeling, chromatin modifications and exchange of chromatin components and is linked to DNA methylation in some cases. In plants and other organisms, chromatin proteins control many developmental pathways, integrate changes in the environment and can confer a cellular memory of these cues. Here, we review the molecular mechanisms that provide a dynamic regulation of chromatin in a cell. In addition, we discuss how chromatin needs to be flexibly regulated during plant growth to confer stable expression states that can occasionally be reset, e.g., owing to changes in the environment and progression of development. [ABSTRACT FROM AUTHOR]

Abstract: Little research on the epigenetic phenomenon of DNA methylation has been performed with invertebrates. However, a few studies have shown that effects of transient chemical exposure can be transferred to non-exposed generations through epigenetic inheritance. If this is a wide-spread phenomenon it may have major consequences for current ecological risk assessments. The presence of DNA methylation in Daphnia magna has only very recently been demonstrated, although not quantified. In the present study, the overall content of 5-methyl-2′-deoxycytidine (5mdC) in the DNA of D. magna was determined. Additionally, the effect of transgenerational Zn exposure on the 5mdC content was assessed. An optimized LC-MS-MS method proved to be very suitable for measuring overall levels of 5mdC in relatively small samples of D. magna DNA. The average [5mdC]/[dG] ratio ranged from 0.13% to 0.81%. A slight but significant decrease in DNA methylation was found in the offspring (F1) of Zn exposed daphnids in the parental generation. However, this effect did not propagate into the next generation (F2). The presence of DNA methylation in D. magna and the finding that different exposure histories can entail different levels of methylation, open the way for further investigations on the implications of epigenetics in aquatic toxicology. [Copyright &y& Elsevier]

Abstract: DNA methylation is a heritable epigenetic modification of cytosine residues within CpG dinucleotides associated with the modulation of gene expression and found at 20–30 million sites throughout the mammalian genome. The methylation of DNA is catalyzed by DNA (cytosine-5)-methyltransferases (DNMTs), regulates genes during development and plays a role in genomic imprinting and X inactivation. Abnormalities in DNA methylation lead to growth and behavioral abnormalities as well as cancer. Genomic methylation patterns are acquired in the germline and then further modified during embryogenesis. Methylation in the male germline is unique in comparison to that in somatic tissues, begins in the fetal gonad before birth, and is completed during postnatal spermatogenesis. In rodents, altered expression of the DNMTs through gene-targeting or drug treatment is associated with abnormal DNA methylation patterns in germ cells and perturbations in spermatogenesis. In man altered sperm DNA methylation patterns have been reported in individuals with oligospermia. [Copyright &y& Elsevier]