The effect of exposure to carcinogenic metals on histone tail modifications and gene expression in human subjects

The precise mechanisms by which nickel and arsenic compounds exert their carcinogenic properties are not completely understood. In recent years, alterations of epigenetic mechanisms have been implicated in the carcinogenesis of compounds of these two metals. In vitro exposure to certain nickel or arsenic compounds induces changes in both DNA methylation patterns, as well as, in the levels of posttranslational modifications of histone tails. Changes in DNA methylation patterns have been reported in human subjects exposed to arsenic. Here we review our recent reports on the alterations in global levels of posttranslational histone modifications in peripheral blood mononuclear cells (PBMCs) of subjects with occupational exposure to nickel and subjects exposed to arsenic in their drinking water. Occupational exposure to nickel was associated with an increase in H3K4me3 and decrease in H3K9me2. A global increase in H3K9me2 and decrease in H3K9ac was found in subjects exposed to arsenic. Additionally, exposure to arsenic resulted in opposite changes in a number of histone modifications in males when compared with females in the arsenic population. The results of these two studies suggest that exposure to nickel or arsenic compounds, and possibly other carcinogenic metal compounds, can induce changes in global levels of posttranslational histone modifications in peripheral blood mononuclear cells.     

Connections between epigenetic gene silencing and human disease

Alterations in epigenetic gene regulation are associated with human disease. Here, we discuss connections between DNA methylation and histone methylation, providing examples in which defects in these processes are linked with disease. Mutations in genes encoding DNA methyltransferases and proteins that bind methylated cytosine residues cause changes in gene expression and alterations in the patterns of DNA methylation. These changes are associated with cancer and congenital diseases due to defects in imprinting. Gene expression is also controlled through histone methylation. Altered levels of methyltransferases that modify lysine 27 of histone H3 (K27H3) and lysine 9 of histone H3 (K9H3) correlate with changes in Rb signaling and disruption of the cell cycle in cancer cells. The K27H3 mark recruits a Polycomb complex involved in regulating stem cell pluripotency, silencing of developmentally regulated genes, and controlling cancer progression. The K9H3 methyl mark recruits HP1, a structural protein that plays a role in heterochromatin formation, gene silencing, and viral latency. Cells exhibiting altered levels of HP1 are predicted to show a loss of silencing at genes regulating cancer progression. Gene silencing through K27H3 and K9H3 can involve histone deacetylation and DNA methylation, suggesting cross talk between epigenetic silencing systems through direct interactions among the various players. The reversible nature of these epigenetic modifications offers therapeutic possibilities for a wide spectrum of disease.     

Computer- and structure-based lead design for epigenetic targets

The term epigenetics is defined as inheritable changes that influence the outcome of a phenotype without changes in the genome. Epigenetics is based upon DNA methylation and posttranslational histone modifications. While there is much known about reversible acetylation as a posttranslational modification, research on reversible histone methylation is still emerging, especially with regard to drug discovery. As aberrant epigenetic modifications have been linked to many diseases, inhibitors of histone modifying enzymes are very much in demand. This article will summarize the progress on small molecule epigenetic inhibitors identified by structure- and computer-based approaches.     

Aberrant epigenetic landscape in cancer: how cellular identity goes awry

Appropriate patterns of DNA methylation and histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases, such as cancer. Our aim here is to provide an overview of how epigenetic factors, including genomic DNA methylation, histone modifications, and microRNA regulation, contribute to normal development, paying special attention to their role in regulating tissue-specific genes. In addition, we summarize how these epigenetic patterns go awry during human cancer development. The possibility of "resetting" the abnormal cancer epigenome by applying pharmacological or genetic strategies is also discussed.     

The epigenetic face of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an archetypical systemic, autoimmune inflammatory disease characterized by the production of autoantibodies to multiple nuclear Ags. Apoptotic defects and impaired removal of apoptotic cells contribute to an overload of autoantigens that become available to initiate an autoimmune response. Besides the well-recognized genetic susceptibility to SLE, epigenetic factors are important in the onset of the disease, as even monozygotic twins are usually discordant for the disease. Changes in DNA methylation and histone modifications, the major epigenetic marks, are a hallmark in genes that undergo epigenetic deregulation in disease. In SLE, global and gene-specific DNA methylation changes have been demonstrated to occur. Moreover, histone deacetylase inhibitors reverse the skewed expression of multiple genes involved in SLE. In the present study, we discuss the implications of epigenetic alterations in the development and progression of SLE and how epigenetic drugs constitute a promising source of therapy to treat this disease.     

Dynamic regulation of DNA methylation and histone modifications in response to abiotic stresses in plants

DNA methylation and histone modification are evolutionarily conserved epigenetic modifications that are crucial for the expression regulation of abiotic stress-responsive genes in plants. Dynamic changes in gene expression levels can result from changes in DNA methylation and histone modifications. In the last two decades, how epigenetic machinery regulates abiotic stress responses in plants has been extensively studied. Here, based on recent publications, we review how DNA methylation and histone modifications impact gene expression regulation in response to abiotic stresses such as drought, abscisic acid, high salt, extreme temperature, nutrient deficiency or toxicity, and ultraviolet B exposure. We also review the roles of epigenetic mechanisms in the formation of transgenerational stress memory. We posit that a better understanding of the epigenetic underpinnings of abiotic stress responses in plants may facilitate the design of more stress-resistant or -resilient crops, which is essential for coping with global warming and extreme environments.     

Prenatal nutrition and the risk of adult obesity: Long-term effects of nutrition on epigenetic mechanisms regulating gene expression

Solid epidemiological evidence indicates that part of the risk of obesity in adulthood could be programmed during prenatal development by the quality of maternal nutrition. Nevertheless, the molecular mechanisms involved are mostly unknown, which hinders our capacity to develop effective intervention policies. Here, we discuss the hypothesis that mechanisms underlying prenatal programming of adult risk are epigenetic and sensitive to environmental cues such as nutrition. While the information encoded in DNA is essentially stable, regulatory epigenetic mechanisms include reversible, covalent modifications of DNA and chromatin, such as methylation, acetylation etc. It is known that dietary availability of methyl donors has an impact on the patterns of gene expression by affecting DNA methylation at regulatory regions, a likely basis for reprogramming developmental plasticity. The Agouti and Axin-fused genes, as well as the embryonic growth factor IGF2/H19 locus are examples of diet-induced modulation of phenotypic traits by affecting methylation of gene-regulatory regions. Recent work has evidenced an unsuspected role for chromatin as metabolic sensor. Chromatin is susceptible to a number of post-translational modifications that modulate gene expression, among them the GlcNAcylation of histone proteins and other epigenetic regulators. Intracellular levels of the precursor molecule UDP-GlcNAc, and hence the degree of global chromatin GlcNAcylation, depend on the energetic state of the cell, making GlcNAcylation a functional link between nutrition and regulation of gene expression. Dietary interference with these regulatory mechanisms could effectively counteract the early-life programming of adult risk.     

A diverse epigenetic landscape at human exons with implication for expression

DNA methylation is an important epigenetic marker associated with gene expression regulation in eukaryotes. While promoter methylation is relatively well characterized, the role of intragenic DNA methylation remains unclear. Here, we investigated the relationship of DNA methylation at exons and flanking introns with gene expression and histone modifications generated from a human fibroblast cell-line and primary B cells. Consistent with previous work we found that intragenic methylation is positively correlated with gene expression and that exons are more highly methylated than their neighboring intronic environment. Intriguingly, in this study we identified a unique subset of hypomethylated exons that demonstrate significantly lower methylation levels than their surrounding introns. Furthermore, we observed a negative correlation between exon methylation and the density of the majority of histone modifications. Specifically, we demonstrate that hypo-methylated exons at highly expressed genes are associated with open chromatin and have a characteristic histone code comprised of significantly high levels of histone markings. Overall, our comprehensive analysis of the human exome supports the presence of regulatory hypomethylated exons in protein coding genes. In particular our results reveal a previously unrecognized diverse and complex role of the epigenetic landscape within the gene body.     

Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation

Linker histone H1 plays an important role in chromatin folding in vitro. To study the role of H1 in vivo, mouse embryonic stem cells null for three H1 genes were derived and were found to have 50% of the normal level of H1. H1 depletion caused dramatic chromatin structure changes, including decreased global nucleosome spacing, reduced local chromatin compaction, and decreases in certain core histone modifications. Surprisingly, however, microarray analysis revealed that expression of only a small number of genes is affected. Many of the affected genes are imprinted or are on the X chromosome and are therefore normally regulated by DNA methylation. Although global DNA methylation is not changed, methylation of specific CpGs within the regulatory regions of some of the H1 regulated genes is reduced. These results indicate that linker histones can participate in epigenetic regulation of gene expression by contributing to the maintenance or establishment of specific DNA methylation patterns.     

Role of epigenetic reprogramming of host genes in bacterial pathogenesis

The genomes are regularly targeted by epigenetic regulatory mechanisms (DNA methylation, histone modifications, binding of regulatory proteins) in infected cells. In addition, proteins encoded by microbial genomes may disturb the action of a set of cellular promoters by interacting with the same epi-regulatory machinery. The outcome of this may result in epigenetic dysregulation and subsequent cellular dysfunctions that may manifest in or contribute to the development of pathological changes. How epigenetic methylation decorations on DNA and histones are started and established remains largely unknown. The inherited nature of these processes in regulation of genes suggests that they could play key roles in chronic diseases associated with microbial persistence; they might also explain so-called hit-and-run phenomena in infectious disease pathogenesis. Microbes infecting mammals may cause diseases by causing hyper-methylation of key cellular promoters at CpG di-nucleotides and may induce pathological changes by epigenetic reprogramming of host cells they are interacting with elucidation of the epigenetic consequences of microbe–host interactions may have important therapeutic implications because epigenetic processes can be reverted and elimination of microbes inducing patho-epigenetic changes may prevent disease development.     

Current advances in epigenetic modification and alteration during mammalian ovarian folliculogenesis

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 are 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).     

Position effect variegation and epigenetic modification of a transgene in a pig model

Sequences proximal to transgene integration sites are able to regulate transgene expression, resulting in complex position effect variegation. Position effect variegation can cause differences in epigenetic modifications, such as DNA methylation and histone acetylation. However, it is not known which factor, position effect or epigenetic modification, plays a more important role in the regulation of transgene expression. We analyzed transgene expression patterns and epigenetic modifications of transgenic pigs expressing green fluorescent protein, driven by the cytomegalovirus (CMV) promoter. DNA hypermethylation and loss of acetylation of specific histone H3 and H4 lysines, except H4K16 acetylation in the CMV promoter, were consistent with a low level of transgene expression. Moreover, the degree of DNA methylation and histone H3/H4 acetylation in the promoter region depended on the integration site; consequently, position effect variegation caused variations in epigenetic modifications. The transgenic pig fibroblast cell lines were treated with DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine and/or histone deacetylase inhibitor trichostatin A. Transgene expression was promoted by reversing the DNA hypermethylation and histone hypoacetylation status. The differences in DNA methylation and histone acetylation in the CMV promoter region in these cell lines were not significant; however, significant differences in transgene expression were detected, demonstrating that variegation of transgene expression is affected by the integration site. We conclude that in this pig model, position effect variegation affects transgene expression.     

Poly-ADP-Ribose (PAR) as an epigenetic flag

Epigenetics is the study of hereditable chromatin modifications, such as DNA methylation, histone modifications, and nucleosome-remodelling, which occur without alterations to the DNA sequence. The establishment of different epigenetic states in eukaryotes depends on regulatory mechanisms that induce structural changes in chromatin in response to environmental and cellular cues. Two classes of enzymes modulate chromatin accessibility: chromatin-covalent modifiers and ATP-dependent chromatin remodelling complexes. The first class of enzymes catalyzes covalent modifications of DNA as well as the amino- and carboxy-terminal tails of histones, while the second uses the energy of ATP hydrolysis to reposition nucleosomes along the chromatin fibers or to incorporate histone variants. Thus, epigenetic modifications are reversible nuclear reactions. In the last decade, many studies have strongly indicated that alterations in epigenetic modifications may contribute to the onset and progression of a variety of human diseases such as cancer. Therefore, the enzymes responsible for these chromatin changes are becoming attractive therapeutic targets.     

Unraveling the epigenetic code of cancer for therapy

Alterations in the genome and the epigenome are common in most cancers. Changes in epigenetic signatures, including aberrant DNA methylation and histone deacetylation, are among the most prevalent modifications in cancer and lead to dramatic changes in gene expression patterns. Because DNA methylation and histone deacetylation are reversible processes, they have become attractive as targets for cancer epigenetic therapy, both as single agents and as 'enhancing' agents for other treatment strategies. In this review we discuss our current view of the mammalian epigenome, this view has changed over the years because of the availability of novel technologies. We further demonstrate how the profound understanding of epigenetic alterations in cancer will help develop novel strategies for epigenetic therapies.     

Genetic and epigenetic effects of environmental arsenicals

Environmental arsenic compounds and their methylated metabolites do not form adducts with DNA, but do cause oxidative DNA damage. Chromosome aberrations are seen at toxic concentrations. Genetic effects that occur at non-toxic concentrations include aneuploidy, comutagenesis (resulting from indirect effects on DNA repair), and delayed mutagenesis (probably secondary to aneuploidy and/or epigenetic effects). Effects of trivalent arsenicals on poly(ADP ribose) polymerase and P53 activation may mediate effects on DNA repair and aneuploidy. A growing literature points to the epigenetic effects of arsenic compounds in cells and in vivo. A review of the current literature on DNA methylation, histone modifications and microRNA effects is presented.