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The ability to sequence the genomes and epigenomes of cancers has provided a wealth of information about the scope of epigenetic damage in cancer cells and also offers new players that may contribute to disease onset and progression. These data emphasize that an entire spectrum of epigenetic mechanisms is subject to dysregulation in cancers including DNA methylation, histone modifications, histone variant usage, small and noncoding RNA molecules, together with nucleosomes and higher-order chromatin structures and their associated machinery. Not least, the discovery that genetic mutations in chromatin-modifying proteins are occurring at high frequency and across many types of cancers highlights the importance of understanding the interplay between epigenetic and genetic changes in cancers. It remains important to consider epigenetic defects within context; then, there will be great potential to identify the key epigenetic events leading to cancer initiation and development.

It was hoped that the Human Genome Project would launch a new era for medicine, providing new insights into the mechanism, prevention, diagnosis, treatment, and prognosis of numerous diseases. However, even as it was being completed, scientists were realizing that there was a layer of epigenetic code not explained by Mendelian inheritance, but which helped control our subtly balanced life support system. To date, knowledge about epigenetics in biological processes is rapidly increasing due to the discovery of new epigenetic code and the development of new techniques for epigenome profiling. For example, new epigenetic alterations related to normal development and disease pathogenesis are continuously discovered. These variants are involved in DNA methylation, histone modification, histone variation, and control of noncoding RNAs. Owing to these discoveries, the US Food and Drug Administration have approved at least seven epigenetic drugs and more agents are on the way. Furthermore, mounting reference epigenomes from healthy and diseased human cells are being mapped under the concerted effort of the International Human Epigenome Consortium, which promises to be a great resource for disease diagnostics, prognostics, and clinical therapeutics. Eventually, with the personalized epigenetic information, the precision medicine will help deliver the right treatment to the individual patient at the right time, which is the ultimate goal of future medical epigenetics.

The term epigenetics describes the study of relatively stable changes in gene expression which occur without changes of the DNA sequence. The three best described mechanisms are: 1, cytosine methylation at cytosine-guanine dinucleotides of the DNA; 2, histone modifications (such as acetylation, methylation, and phosphorylation); and 3, micro RNA interference. The interplay between DNA methylation, histone modifications and micro RNA interference functions as regulatory complex which allows to fine tune cell specific gene expression in cell differentiation and organ development, and which is sensible to environmental signals. More precisely, the sequence of histone deacetylation, histone methylation and DNA methylation has been discussed as ‘molecular switch’ which modifies long-term gene expression patterns and chromatin activity states. In neurons, this epigenetic switch is involved in the transformation of short-term into long-term memory and is propagated across brain areas via neural activity (‘systems heritability of epigenetic marks’, Sultan Day/David Sweatt). Other evidence indicates sensibility of epigenetic marks towards behavioral (maternal care), chemical (nutrients) and hormonal (stress hormones) influences.In regard to psychobiological development, epidemiological and clinical data shows that early life stress affects later stress responsivity, emotion regulation and cognitive functions, as well as life-time vulnerability to psychopathology. Evidence indicates a multi-level relationship between early life stress, neural structure and function and mental and general health connected via the HPA axis and its feedback mechanisms over time. Associations between early life stress and changes in brain regions involved in stress regulation have been repeatedly reported, including a small hippocampus, reduced medial prefrontal cortical volume, reduced orbitofrontal cortical volume, and increased amygdala volume. Further alterations related to early life stress in humans include glucocorticoid resistance, increased levels of inflammation, increased central corticotropin-releasing hormone activity and decreased levels of oxytocin. These general observations in humans are supported by a more detailed picture derived from animal studies of early life stress. Research in rodents using a maternal stress and/or maternal separation paradigm showed consistently that pre- or postnatal stress results in elevated HPA axis activity as well as structural and functional changes of neural networks in brain regions involved in neuroendocrine control, vigilance and emotion regulation, and that these changes correspond with distinct and persistent physiological response types and behavioral patterns in the adult individual. In addition, the differences between stress responsivity and behavior following early life stress are associated with epigenetic differences. In the context of early life stress, epigenetic modifications represent a plausible pathway by which early experiences are integrated into the molecular regulation of adult hormonal responses and behavior. Life-time stability of epigenetic changes, stress response types and behavioral patterns together with the time-dependence of the induced changes – early in life – indicate an evolutionary and developmental function of the underlying mechanisms: It seems that during a critical period (developmental window) early in life the stress response undergoes adaptive changes regulated via epigenetic programming. Furthermore, the mechanisms involved in epigenetic programming of the HPA axis also seem to impact neural and mental development in general. Preliminary results from animal models indicate, that early life stress affects cognitive abilities such as spatio-visual learning and memory, and that these cognitive differences are associated with epigenetic differences such as different methylation patterns. This would indicate a broad and unspecific developmental impact of pre- and postnatal stress and corresponding epigenetic programming during critical periods of brain development.Thus, epigenetic mechanisms seem to function as ‘developmental switch’, explaining the stability of long-term effects of early life stress by programming central feedback mechanisms of the HPA axis and other neural networks. The pathway very likely involves a ‘dual activation’ of the epigenetic machinery: First, acute HPA axis activity during critical periods of neurogenesis generally primes the epigenetic machinery in brain tissue for reprogramming effects via the release of glucocorticoids. Second, sensory induced activation of neural networks transforms the epigenetic regulatory system in target brain areas, so that stressor specific adaptive to maladaptive functional modifications are maintained.The paper outlines the possible underlying molecular mechanisms of epigenetic programming in psychobiological development according to the dual-activitation theory and summarizes the accumulated evidence. The dual-activation theory specifies epigenetic programming in psychobiological development as the result of an interplay between HPA axis activity and neural activity following sensory stimulation in critical periods early in life. Implications for the treatment of stress dependent psychopathologies are discussed.

DNA methylation and modifications of histones, such as reversible acetylation and methylation on lysine residues, are very important for epigenetic regulation. Methyl-lysine binding proteins recognize distinct lysine residues within proteins and they distinguish between different levels of methylation. Signaling events and biological outcome of histone methylation are mediated by methyl-lysine binding proteins which are also referred to as readers of the epigenetic code. The involvement of methyl-lysine readers in different diseases makes them highly promising drug targets that might result in novel therapeutic strategies in the future. In this chapter, early drug discovery approaches in this field are introduced and small-molecule inhibitors of the interaction of reader proteins and their histone-binding partners are presented. Furthermore, this chapter reviews the literature on reader proteins that are reported to function as oncoproteins and thus display potential drug targets.

The epigenomic era has revealed a well-connected network of molecular processes that shape the chromatin landscape. These processes comprise abnormal methylomes, transcriptosomes, genome-wide histone post-transcriptional modifications patterns, histone variants, and noncoding RNAs. The mapping of these processes in large scale by chromatin immunoprecipitation sequencing and other methodologies in both cancer and normal cells reveals novel therapeutic opportunities for anticancer intervention. The goal of this minireview is to summarize pharmacological strategies to modify the epigenetic landscape of cancer cells. These approaches include the use of novel small molecule inhibitors of epigenetic processes specifically deregulated in cancer cells and the design of engineered proteins able to stably reprogram the epigenetic code in cancer cells in a way that is similar to normal cells.

Emerging evidence suggests that epigenetic alterations to the genome, including DNA methylation, histone modifications, and microRNA synthesis are important mechanisms underlying several physiological and pathological processes in brain. In this review, we introduce the reader to epigenetic mechanisms and describe a potential role for dynamic epigenetic changes in memory formation, aging, and mediating addictive behaviors via long-lasting changes in gene expression. We also discuss evidence for a “histone code” in the central nervous system that mediates synaptic plasticity, learning, and memory. Collectively, the current rapid growth in epigenetic research could potentially revolutionize our understanding of the molecular changes associated with several neuropsychiatric diseases. Moreover, these studies demonstrate that alteration of the histone modification and/or the DNA methylation might prove to be potent candidates for therapeutic interventions.

New data are revealing a complex landscape of gene regulation shaped by chromatin states that extend into the bodies of transcribed genes and associate with distinct RNA elements such as exons, introns and polyadenylation sites. Exons are characterized by increased levels of nucleosome positioning, DNA methylation and certain histone modifications. As pre-mRNA splicing occurs co-transcriptionally, changes in the transcription elongation rate or epigenetic marks can influence exon splicing. These new discoveries broaden our understanding of the epigenetic code and ascribe a novel role for chromatin in controlling pre-mRNA processing. In this review, we summarize the recently discovered interplay between the modulation of chromatin states and pre-mRNA processing with the particular focus on how these processes communicate with one another to control gene expression.

Epigenetic marks in an organism can be altered by environmental factors throughout life. Although changes in the epigenetic code can be positive, some are associated with severe diseases, in particular, cancer and neuropsychiatric disorders. Recent evidence has indicated that certain epigenetic marks can be inherited, and reshape developmental and cellular features over generations. This review examines the challenging possibility that epigenetic changes induced by environmental factors can contribute to some of the inheritance of disease and disease risk. This concept has immense implications for the understanding of biological functions and disease etiology, and provides potential novel strategies for diagnosis and treatment. Examples of epigenetic inheritance relevant to human disease, such as the detrimental effects of traumatic stress or drug/toxic exposure on brain functions, are reviewed. Different possible routes of transmission of epigenetic information involving the germline or germline-independent transfer are discussed, and different mechanisms for the maintenance and transmission of epigenetic information like chromatin remodeling and small noncoding RNAs are considered. Future research directions and remaining major challenges in this field are also outlined. Finally, the adaptive value of epigenetic inheritance, and the cost and benefit of allowing acquired epigenetic marks to persist across generations is critically evaluated.

Investigations on gene variants as milestones in the development of schizophrenia have not fulfilled the enormous, initial expectations. Neither candidate gene approaches trying to associate single genes with the disorder, nor genome-wide association studies (GWAS), that have been welcomed more recently with great enthusiasm, could end the general disappointment associated with these strategies. Owing to very large numbers of samples and most advanced sequencing technologies, some variants have been found but their effects, even in combination are very small. In summary, most of the tentative heritability of schizophrenia remains unexplained. More hope to find mechanisms connecting genes with the disorder lies in analyses of the epigenome with technologies developed during the last 10 or 15 years and undergoing more and more refinement recently. Although investigations on interactions between DNA methylation patterns and histone modifications will probably be the greatest challenge in molecular genetics for the next decades, they appear to be the most promising approaches on complex brain disorders that typically show a high dependence on environmental factors.

Through epigenetic modifications, specific long-term phenotypic consequences can arise from environmental influence on slowly evolving genomic DNA. Heritable epigenetic information regulates nucleosomal arrangement around DNA and determines patterns of gene silencing or active transcription. One of the greatest challenges in the study of epigenetics as it relates to disease is the enormous diversity of proteins, histone modifications and DNA methylation patterns associated with each unique maladaptive phenotype. This is further complicated by a limitless combination of environmental cues that could alter the epigenome of specific cell types, tissues, organs and systems. In addition, complexities arise from the interpretation of studies describing analogous but not identical processes in flies, plants, worms, yeast, ciliated protozoans, tumor cells and mammals. This review integrates fundamental basic concepts of epigenetics with specific focus on how the epigenetic machinery interacts and operates in continuity to silence or activate gene expression. Topics covered include the connection between DNA methylation, methyl-CpG-binding proteins, transcriptional repression complexes, histone residues, histone modifications that mediate gene repression or relaxation, histone core variant stability, H1 histone linker flexibility, FACT complex, nucleosomal remodeling complexes, HP1 and nuclear lamins.

Problem statement: Histone modifications are required for chromatin a ctivities and are believed to form an epigenetic code. However, the i nheritance of the histone post-translational modifications remains unclear. Approach and Results: The aim of this study was to evaluate the histone modifications throughout the cell cycle and to determine whether the histone marks are transferred to daughter cells. Using the naturally synchronous model system Physarum polycephalum and Western blotting analyses, we showed that the h istone modifications are not exclusive of the cell cycle stage. Importantly, we also demonstrated that during mitosis, a substantial fraction of the acetylation and the methylation marks of the histon e H3 and H4 is removed. Conclusion: The results illustrate that a part of the histone modifications are displaced during mitosis and thus failed to ex hibit an inheritance to daughter cells as proposed for th e epigenetic marks.

Since its discovery more than 50 years ago, post-translational modification (PTM) of proteins via methylation has grown in prominence, its involvement having been recognised in a number of central processes in the cell. Of these, the best characterised is its role in the epigenetic code. However, there is increasing evidence that its role extends far beyond this and we propose that it is a key regulator in interactome dynamics. In this review, we focus on the role of methylation in regulating protein-protein interactions and illustrate, by providing a broad-scale summary of our current knowledge of methylation and its impact on systems biology, how this can ultimately affect interactome dynamics. We describe the variety of analytical techniques available for the study of the methylproteome, comment on their advantages and limitations, and consider how these tools can help elucidate how methylation regulates the dynamics of the interactome. The insights gained from methyltransferase-substrate networks will be summarised and the ability of protein methylation to facilitate or block protein-protein interactions as well as their interplay with other post-translational modifications, in particular phosphorylation, is highlighted. Finally, the importance of methylation in pathology-associated protein interaction networks will be discussed using examples involving human diseases and the p53 protein.

The adult brain contains a reservoir of neural stem cells (NSCs) that generates functional neurons in a process called adult neurogenesis. Integration of new neurons into mature neural circuits maintains brain tissue homeostasis essential for learning, olfaction and behavior. Even subtle disruptions in NSC self-renewal/differentiation can result in substantial changes in neuronal production rates, contributing to neuropsychiatric symptoms, cognitive dysfunction and epilepsy. Recent studies have revealed pivotal roles for epigenetic regulators of gene expression. Epigenetic and genetic regulation allows a rich array of possibilities to fine-tune neuronal gene expression and offers potential therapeutic opportunities to modulate brain function related to adult neurogenesis. Here we discuss the role of epigenetic mechanisms underlying NSC fate and translational strategies for the future.

Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined DNA sequences are uniquely suited to answer such questions and could provide potent (bio)medical tools. Toward the goal of gene-specific GEM by overwriting epigenetic marks (Epigenetic Editing, EGE), instructive epigenetic marks need to be identified and their writers/erasers should then be fused to gene-specific DNA binding domains. The appropriate epigenetic mark(s) to change in order to efficiently modulate gene expression might have to be validated for any given chromatin context and should be (mitotically) stable. Various insights in such issues have been obtained by sequence-specific targeting of epigenetic enzymes, as is presented in this review. Features of such studies provide critical aspects for further improving EGE. An example of this is the direct effect of the edited mark versus the indirect effect of recruited secondary proteins by targeting epigenetic enzymes (or their domains). Proof-of-concept of expression modulation of an endogenous target gene is emerging from the few EGE studies reported. Apart from its promise in correcting disease-associated epi-mutations, EGE represents a powerful tool to address fundamental epigenetic questions.

Genomic imprinting is an epigenetic process leading to parental-specific expression of one to two percent of mammalian genes that offers one of the best model systems for a molecular analysis of epigenetic regulation in development and disease. In the twenty years since the first imprinted gene was identified, this model has had a significant impact on decoding epigenetic information in mammals. So far it has led to the discovery of long-range cis-acting control elements whose epigenetic state regulates small clusters of genes and of unusual macro noncoding RNAs (ncRNAs) that directly repress genes in cis, and critically, it has demonstrated that one biological role of DNA methylation is to allow expression of genes normally repressed by default. This review describes the progress in understanding how imprinted protein-coding genes are silenced; in particular, it focuses on the role of macro ncRNAs that have broad relevance as a potential new layer of regulatory information in the mammalian genome.

Post-translational modifications of histones are critical not only for local regulation of gene expression, but also for higher-order structure of the chromosome and genome organization in general. These modifications enable a preset state to be maintained over subsequent generations and thus provide an epigenetic level of regulation. Heterochromatic regions of the genome are epigenetically regulated to maintain a ‘‘silent state’’ and protein coding genes inserted into these regions are subject to the same epigenetic silencing. The fission yeast Schizosaccharomyces pombe has well characterized regions of heterochromatin and has proven to be a powerful model for elucidation of epigenetic silencing mechanisms. Research in S. pombe led to the breakthrough discovery that epigenetic silencing is not solely a chromatin-driven transcriptional repression and that RNA interference of nascent transcripts can guide epigenetic silencing and associated histone modifications. Over the last 10 years, an eloquent integration of genetic and biochemical studies have greatly propelled our understanding of major players and effector complexes for regulation of RNAi-mediated epigenetic silencing in S. pombe. Here, we review recent research related to regulation of the epigenetic state in S. pombe heterochromatin, focusing specifically on the mechanisms by which transcription and RNA processing interact with the chromatin modification machinery to maintain the epigenetically silent state.

The advances of high throughput profiling methods, such as microarray gene profiling and RNA-seq, have enabled researchers to identify thousands of differentially expressed genes under a certain perturbation. Much work has been done to understand the genetic factors that contribute to the expression changes by searching the over-represented regulatory motifs in the promoter regions of these genes. However, the changes could also be caused by epigenetic regulation, especially histone modifications, and no web server has been constructed to study the epigenetic factors responsible for gene expression changes. Here, we pre-sent a web tool for this purpose. Provided with different categories of genes (e.g., up-regulated, down-regulated or unchanged genes), the server will find epigenetic factors responsible for the difference among the categories and construct an epigenetic regulatory network. Furthermore, it will perform co-localization analyses between these epigenetic factors and transcription factors, which were collected from large scale experimental ChIP-seq or computational predicted data. In addition, for users who want to analyze dynamic change of a histone modification mark under different cell conditions, the server will find direct and indirect target genes of this mark by integrative analysis of experimental data and computational prediction, and present a regulatory network around this mark. Both networks can be visualized by a user friendly interface and the data are downloadable in batch. The server currently supports 12 cell types in human, including ESC and CD4+ T cells, and will expand as more public data are available. It also allows user to create a self-defined cell type, upload and analyze multiple ChIP-seq data. It is freely available to academic users at http://jjwanglab.org/EpiRegNet.

Although all nucleated cells within a multicellular organism contain a complete copy of the genome, cell identity relies on the expression of a specific subset of genes. Therefore, when cells divide they must not only copy their genome to their daughters, but also ensure that the pattern of gene expression present before division is restored. While the carrier of this epigenetic memory has been a topic of much research and debate, post-translational modifications of histone proteins have emerged in the vanguard of candidates. In this paper we examine the mechanisms by which histone post-translational modifications are propagated through DNA replication and cell division, and we critically examine the evidence that they can also act as vectors of epigenetic memory. Finally, we consider ways in which epigenetic memory might be disrupted by interfering with the mechanisms of DNA replication.

Although the critical role for epigenetic mechanisms in development and cell differentiation has long been appreciated, recent evidence reveals that these mechanisms are also employed in post-mitotic neurons as a means of consolidating, and stabilizing cognitive-behavioral memories. In this review, we discuss evidence for an “epigenetic code” in the central nervous system that mediates synaptic plasticity, learning, and memory. We consider how specific epigenetic changes are regulated and may interact with each other during memory formation, and how these changes manifest functionally at the cellular and circuit levels. We also describe a central role for mitogen-activated protein kinases in controlling chromatin signaling in plasticity and memory. Finally, we consider how aberrant epigenetic modifications may lead to cognitive disorders that affect learning and memory, and review the therapeutic potential of epigenetic treatments for the amelioration of these conditions.

High-throughput genomic sequencing and quantitative mass spectrometry (MS)-based proteomics technology have recently emerged as powerful tools, increasing our understanding of chromatin structure and function. Both of these approaches require substantial investments and expertise in terms of instrumentation, experimental methodology, bioinformatics, and data interpretation and are, therefore, usually applied independently from each other by dedicated research groups. However, when applied reiteratively in the context of epigenetics research these approaches are strongly synergistic in nature.

Emerging evidence points to a role for long non-coding RNAs in the modulation of epigenetic states and transcription in human cells. New insights, using various forms of small non-coding RNAs, suggest that a mechanism of action is operative in human cells, which utilizes non-coding RNAs to direct epigenetic marks to homology containing loci resulting ultimately in the epigenetic-based modulation of gene transcription. Importantly, insights into this mechanism of action have allowed for certain target sequences, which are either actively involved in RNA mediated epigenetic regulation or targets for non-coding RNA based epigenetic regulation, to be selected. As such, it is now feasible to utilize small antisense RNAs to either epigenetically silence a gene expression or remove epigenetic silencing of endogenous non-coding RNAs and essentially turn on a gene expression. Knowledge of this emerging RNA-based epigenetic regulatory network and our ability to cognitively control gene expression has deep implications in the development of an entirely new area of pharmacopeia.

The establishment and faithful maintenance of epigenetic information in the context of chromatin are crucial for a great number of biologic phenomena, including position effect variegation, Polycomb silencing, X-chromosome inactivation and genomic imprinting. However, mechanisms by which that the correct histone modification patterns propagate into daughter cells during mitotic divisions remain to be elucidated. The partitioning pattern of parental histone H3–H4 tetramers is a critical question toward our understanding of the epigenetic inheritance. In this review, we discuss why the histone H3–H4 tetramer split decision matters.

"Epigenetics" is currently defined as "the inheritance of variation (-genetics) above and beyond (epi-) changes in the DNA sequence". Despite the fact that histones are believed to carry important epigenetic information, little is known about the molecular mechanisms of the inheritance of histone-based epigenetic information, including histone modifications and histone variants. Here we review recent progress and discuss potential models for the mitotic inheritance of histone modifications-based epigenetic information.

Cell reprogramming has been known to accompany cell type-specific epigenetic alterations of the genome. Chromatin structure and dynamics influenced by epigenetic factors such as covalent histone modifications, histone variants, DNA methylation, ncRNAs and chromatin remodeling play an important role in determining cell fate. The rapid progress made with the development of high-throughput technology and the systematic assessment of accumulated data has enabled the identification of previously unknown biological processes and disease states in terms of whole-genome profiles of epigenetic signatures at a high resolution. In this article, we discuss the fundamental advances and challenges over the past several years in our knowledge of chromatin state and gene transcription programs associated with epigenetic changes during cell reprogramming processes. In particular, histone modifications, DNA methylation and transcriptome analyses in genome-scale studies will be reviewed to characterize a functional cross-talk between epigenetic and transcriptional regulations in cell reprogramming.

In mammals, higher order chromatin structures are critical for downsizing the genome (packaging) so that the nucleus can be small. The adjustable density of chromatin also regulates gene expression, thus this post-genetic molecular mechanism is one of the routes by which phenotype is shaped. Phenotypes that arise without a concomitant mutation of the underlying genome are termed epigenetic phenomena. Here we discuss epigenetic phenomena from histone and DNA modification as it pertains to the dynamic regulatory processes of the circadian clock. Epigenetic phenomena certainly explain some regulatory aspects of the mammalian circadian oscillator. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

Epigenetic modification of genomic DNA by methylation is important for defining the epigenome and the transcriptome in eukaryotes as well as in prokaryotes. In prokaryotes, the DNA methyltransferase genes often vary, are mobile, and are paired with the gene for a restriction enzyme. Decrease in a certain epigenetic methylation may lead to chromosome cleavage by the partner restriction enzyme, leading to eventual cell death. Thus, the pairing of a DNA methyltransferase and a restriction enzyme forces an epigenetic state to be maintained within the genome. Although restriction enzymes were originally discovered for their ability to attack invading DNAs, it may be understood because such DNAs show deviation from this epigenetic status. DNAs with epigenetic methylation, by a methyltransferase linked or unlinked with a restriction enzyme, can also be the target of DNases, such as McrBC of Escherichia coli, which was discovered because of its methyl-specific restriction. McrBC responds to specific genome methylation systems by killing the host bacterial cell through chromosome cleavage. Evolutionary and genomic analysis of McrBC homologues revealed their mobility and wide distribution in prokaryotes similar to restriction-modification systems. These findings support the hypothesis that this family of methyl-specific DNases evolved as mobile elements competing with specific genome methylation systems through host killing. These restriction systems clearly demonstrate the presence of conflicts between epigenetic systems.

Epigenetic modifications work in concert with genetic mechanisms to regulate transcriptional activity in normal tissues and are often dysregulated in disease. Although they are somatically heritable, modifications of DNA and histones are also reversible, making them good targets for therapeutic intervention. Epigenetic changes often precede disease pathology, making them valuable diagnostic indicators for disease risk or prognostic indicators for disease progression. Several inhibitors of histone deacetylation or DNA methylation are approved for hematological malignancies by the US Food and Drug Administration and have been in clinical use for several years. More recently, histone methylation and microRNA expression have gained attention as potential therapeutic targets. The presence of multiple epigenetic aberrations within malignant tissue and the abilities of cells to develop resistance suggest that epigenetic therapies are most beneficial when combined with other anticancer strategies, such as signal transduction inhibitors or cytotoxic treatments. A key challenge for future epigenetic therapies will be to develop inhibitors with specificity to particular regions of chromosomes, thereby potentially reducing side effects.

Epigenetic modifications constitute a complex regulatory layer on top of the genome sequence. Pluripotent and differentiated cells provide a powerful system for investigating how the epigenetic code influences cellular fate. High-throughput sequencing of these cell types has yielded DNA methylation maps at single-nucleotide resolution and many genome-wide chromatin maps. In parallel to epigenome mapping efforts, remarkable progress has been made in our ability to manipulate cell states; ectopic expression of transcription factors has been shown to override developmentally established epigenetic marks and to enable routine generation of induced pluripotent stem (iPS) cells. Despite these advances, many fundamental questions remain. The roles of epigenetic marks and, in particular, of epigenetic modifiers in development and in disease states are not well understood. Although iPS cells appear molecularly and functionally similar to embryonic stem cells, more genome-wide studies are needed to define the extent and functions of epigenetic remodeling during reprogramming.

It is generally agreed that adipocytes originate from mesenchymal stem cells in what can be divided into two processes: determination and differentiation. In the past decade, many factors associated with epigenetic signals have been proved to be pivotal for the appropriate timing of adipogenesis progression. A large number of coregulators at critical gene promoters set up specific patterns of DNA methylation, histone acetylation and methylation, and nucleosome rearrangement, that act as an epigenetic code to modulate the correct progress of adipocyte differentiation and adipogenesis during adipogenesis. In this review, we focus on the functions and roles of epigenetic processes in preadipocyte differentiation and adipogenesis.

An epigenetic trait is a stably inherited phenotype resulting from changes in a chromosome without alterations in the DNA sequence. Epigenetic modifications such as DNA methylation, together with covalent modification of histones, are thought to alter chromatin density and accessibility of the DNA to cellular machinery, thereby modulating the transcriptional potential of the underlying DNA sequence. As environmental changes influence epigenetic marks, epigenetics provides an added layer of variation that might mediate the relationship between genotype and internal and external environmental factors. Integration of our knowledge in genetics, epigenomics, and genomics with the use of systems biology tools may present investigators with new, powerful tools to study many complex human diseases such as kidney disease.

In eukaryotic cells, histones are packaged into octameric core particles with DNA wrapping around to form nucleosomes, which are the basic units of chromatin (Kornberg and Thomas, 1974). Multicellular organisms utilise chromatin marks to translate one single genome into hundreds of epigenomes for their corresponding cell types. Inheritance of epigenetic status is critical for the maintenance of gene expression profile during mitotic cell divisions (Allis et al., 2006). During S phase, canonical histones are deposited onto DNA in a replication-coupled manner (Allis et al., 2006). To understand how dividing cells overcome the dilution of epigenetic marks after chromatin duplication, DNA replication coupled (RC) nucleosome assembly has been of great interest. In this review, we focus on the potential influence of RC nucleosome assembly processes on the maintenance of epigenetic status.

Even though every cell in a multicellular organism contains the same genes, the differing spatiotemporal expression of these genes determines the eventual phenotype of a cell. This means that each cell type contains a specific epigenetic program that needs to be replicated through cell divisions, along with the genome, in order to maintain cell identity. The stable inheritance of these programs throughout the cell cycle relies on several epigenetic mechanisms. In this review, DNA methylation and histone methylation by specific histone lysine methyltransferases (KMT) and the Polycomb/Trithorax proteins are considered as the primary mediators of epigenetic inheritance. In addition, non-coding RNAs and nuclear organization are implicated in the stable transfer of epigenetic information. Although most epigenetic modifications are reversible in nature, they can be stably maintained by self-recruitment of modifying protein complexes or maintenance of these complexes or structures through the cell cycle.

Epigenetic modifications play a crucial role in developmental gene regulation. These modifications, being reversible, provide a layer of information over and above the DNA sequence, that has plasticity and leads to the generation of cell type-specific epigenomes during cellular differentiation. In almost all higher eukaryotes, the oocyte provides not only its cytoplasm, mitochondria, maternally deposited RNA and proteins but also an epigenetic component in the form of DNA and histone-modifications. During spermeiogenesis however, most of the histones are replaced by protamines, leading to a loss of the epigenetic component. The sperm is, therefore, viewed as a passive carrier of the paternal genome with a disproportionate, lower epigenetic contribution except for DNA methylation, to the next generation. A recent study overturns this view by demonstrating a locus-specific retention of histones, with specific modifications in the sperm chromatin at the promoters of developmentally important genes. This programmed retention of epigenetic marks with a role in embryonic development is suggested to offset, in some measure, the dominant maternal effect. This new finding helps in addressing the question of epigenetic transmission of environmental and 'lifestyle' experiences across generations and raises the question of 'parental conflict' at the loci that may be differentially marked.

It is well established that aberrant gene regulation by epigenetic mechanisms can develop as a result of pathological processes such as cancer. Methylation of CpG islands is an important component of the epigenetic code and a number of genes become abnormally methylated during tumorigenesis. Some bioactive food components have been shown to have cancer inhibition activities by reducing DNA hypermethylation of key cancer-causing genes through their DNA methyltransferase (DNMT) inhibition properties. The dietary polyphenols, (-)-epigallocatechin- 3-gallate (EGCG) from green tea, genistein from soybean and possibly isothiocyanates from plant foods, are some examples of these bioactive food components modulated by epigenetic factors. The activity of cancer inhibition generated from dietary polyphenols is associated with gene reactivation through demethylation in the promoters of methylation-silenced genes such as p16INK4a and retinoic acid receptor beta. The effects of dietary polyphenols such as EGCG on DNMTs appear to have their direct inhibition by interaction with the catalytic site of the DNMT1 molecule, and may also influence methylation status indirectly through metabolic effects associated with energy metabolism. Therefore, reversal of hypermethylation-induced inactivation of key tumor suppression genes by dietary DNMT inhibitors could be an effective approach to cancer prevention and therapy. In this analysis, we focus on advances in understanding the effects of dietary polyphenols on DNA methylation modulation during the process of cancer development, which will offer exciting new opportunities to explore the role of diet in influencing the biology of cancer and to understand the susceptibility of the human epigenome to dietary effects.

Contains fulltext : 88890.pdf (Publisher’s version ) (Closed access) Mental retardation (MR) is a highly diverse group of cognitive disorders. Gene defects account for about half of all patients and mutations causative for impaired cognition have been identified in more than 400 genes. While there are numerous genetic defects underlying MR, a more limited number of pathways is emerging whose disruption appears to be shared by groups of MR genes. One of these common pathways is composed of MR genes that encode regulators of chromatin structure and of chromatin-mediated transcription regulation. Already more than 20 "epigenetic MR genes" have been identified and this number is likely to increase in the coming years when deep sequencing of exomes and genomes will become commonplace. Prominent examples of epigenetic MR genes include the methyl CpG-binding protein MECP2 and the CREB binding protein, CBP. Interestingly, several epigenetic MR proteins have been found to interact directly with one another or act together in complexes that regulate the local chromatin structure at target genes. Thus, it appears that the functions of individual epigenetic MR proteins converge onto similar biological processes that are crucial to neuronal processes. The next challenge will be to gain more insight into patterns of altered DNA methylation and histone modifications that are caused by epigenetic gene mutations and how these will disrupt the brain-specific expression of target genes. Such research may reveal that a wide variety of mutations in the genetic code result in a more limited number of disruptions to the epigenetic code. If so, this will provide a rationale for therapeutic strategies. 01 juli 2010

The salvage anti-tumoral pathway which implicates the p53-related p73 gene is not yet fully characterized. We therefore attempted to identify the up- and down-stream events involved in the activation of the p73-dependent pro-apoptotic pathway, by focusing on the anti-apoptotic and epigenetic integrator UHRF1 which is essential for cell cycle progression. For this purpose, we analyzed the effects of a known anti-neoplastic drug, thymoquinone (TQ), on the p53-deficient acute lymphoblastic leukemia (ALL) Jurkat cell line. Our results showed that TQ inhibits the proliferation of Jurkat cells and induces G1 cell cycle arrest in a dose-dependent manner. Moreover, TQ treatment triggers programmed cell death, production of reactive oxygen species (ROS) and alteration of the mitochondrial membrane potential (DeltaPsim). TQ-induced apoptosis, confirmed by the presence of hypodiploid G0/G1 cells, is associated with a rapid and sharp re-expression of p73 and dose-dependent changes of the levels of caspase-3 cleaved subunits. These modifications are accompanied by a dramatic down-regulation of UHRF1 and two of its main partners, namely DNMT1 and HDAC1, which are all involved in the epigenetic code regulation. Knockdown of p73 expression restores UHRF1 expression, reactivates cell cycle progression and inhibits TQ-induced apoptosis. Altogether our results showed that TQ mediates its growth inhibitory effects on ALL p53-mutated cells via the activation of a p73-dependent mitochondrial and cell cycle checkpoint signaling pathway which subsequently targets UHRF1.

Plants can apply various strategies to minimize environmental impact. One of the strategies is heritable modifications of gene expression which occur without changing original DNA sequence and are known as epigenetic. Signaling pathway Rb-E2F (retinoblastoma (Rb)-transcription factor E2F/DP) connects the cell cycle with factors, modifying structure of chromatin and DNA. It also co- ordinates cell proliferation and differentiation influenced by external stimuli. The article highlights the activity of Rb-E2F/DP signaling pathway and its connection with the epigenetic changes of DNA in plants. Для минимизации влияния внешней среды растения используют несколько стратегий. Одна из них – наследуемые модификации генной экспрессии, осуществляемые без изменения последовательности нуклеотидов ДНК (эпигенетика). Сигнальный путь Rb-E2F/DP (ретинобластома (Rb)–транскрипционные факторы E2F/DP) связывает клеточный цикл и факторы модификации ДНК и хроматина, а также координирует клеточную пролиферацию и дифференциацию в зависимости от внешних воздействий. В обзоре систематизированы данные об активности сигнального пути Rb-E2F/DP и его связи с эпигенетическими изменениями ДНК у растений. Щоб мінімізувати вплив довкілля рослини використовують декілька стратегій. Одна з них – це наслідування модифікацій генної експресії, які відбуваються без зміни послідовності нуклеотидів ДНК (епігенетика). Сигнальний шлях Rb-E2F/DP (ретинобластома (Rb)–транскрипційнi фактори E2F/DP) поєднує клітинний цикл з факторами модифікації ДНК і хроматину та координує проліферацію і диференціацію клітин залежно від зовнішнього впливу. В огляді систематизовано дані щодо активності сигнального шляху Rb-E2F/DP і його зв’язку з епігенетичними змінами ДНК у рослин.

DNA methylation is an integral part of the mechanism of a remodeling and modification of the chromatin structure. The global complex net of chromatin modification and remodeling reactions is still to be determined, and studies of the mechanisms controlling the epigenetic processes of histone modification and DNA methylation are in their infancy. Cytosine methylation occurs predominantly in CpG sequences of the eukaryotic genome, and it also takes place at symmetric CpHpG and nonsymmetric CpHpH sites (where H is A, T, or C). The modification efficiency of the three types of DNA methylation sites depends on their genomic localization. Different regions of the eukaryotic genome are remarkable for their methylation features: CpG-islands, CpG-island shores, differentially methylated regions of imprinted genes, and regions of nonalternative site-specific modification. The three canonical sites (CpG, CpHpG, and CpHpH) differ in DNA methylation efficiency depending on their nucleotide context. An epigenetic code of DNA methylation can be assumed with context differences playing a specific functional role. The review summarizes the main up-to-date data on the structural and functional features of site-specific cytosine methylation in eukaryotic genomes. Pathogenesis-related alterations in the methylation pattern of the eukaryotic genome are considered.

Although it is widely accepted that the regulation of the chromatin landscape is pivotal to conveying the epigenetic program, it is still unclear how a defined chromatin domain is reproduced following DNA replication and transmitted from one cell generation to the next. Here, we review the multiple mechanisms that potentially affect the inheritance of epigenetic information in somatic cells. We consider models of how histones might be recycled following replication, and discuss the importance of positive-feedback loops, long-range gene interactions and the complex network of trans-acting factors in the transmission of chromatin states.

Epigenetic states are governed by DNA methylation and a host of modifications to histones bound with DNA. These states are essential for proper developmentally regulated gene expression and are perturbed in many diseases. There is great interest in identifying epigenetic mark placement genome-wide and understanding how these marks vary among cell types, with changes in environment or according to health and disease status. Current epigenomic analyses employ bisulfite sequencing and chromatin immunoprecipitation, but query only one type of epigenetic mark at a time, DNA methylation or histone modifications, and often require substantial input material. To overcome these limitations, we established a method using nanofluidics and multi-color fluorescence microscopy to detect DNA and histones in individual chromatin fragments at about 10 Mbp/min. We demonstrated its utility for epigenetic analysis by identifying DNA methylation on individual molecules. This technique will provide the unprecedented opportunity for genome-wide, simultaneous analysis of multiple epigenetic states on single molecules using femtogram quantities of material.

The transition of a cell from one state to another involves large changes in the organization of its chromatin. Indeed, it has become increasingly clear that modifications of the chromatin are the molecular basis of an epigenetic memory that defines cellular identity. Histone variants are likely candidates to contribute to epigenetic regulations. Genome-wide profiling of the unusual macroH2A histone variants and the identification of interacting proteins provided important clues to their molecular and physiological function.

Epigenetic changes of gene expression can potentially be reversed by developmental programs, genetic manipulation, or pharmacological interference. However, a case of transcriptional gene silencing, originally observed in tetraploid Arabidopsis thaliana plants, created an epiallele resistant to many mutations or inhibitor treatments that activate many other suppressed genes. This raised the question about the molecular basis of this extreme stability. A combination of forward and reverse genetics and drug application provides evidence for an epigenetic double lock that is only alleviated upon the simultaneous removal of both DNA methylation and histone methylation. Therefore, the cooperation of multiple chromatin modifications can generate unanticipated stability of epigenetic states and contributes to heritable diversity of gene expression patterns.

In plants and animals, gene expression can be altered by changes that do not alter the sequence of nucleotides in DNA but rather modify the chemical structure of either the DNA or the histones that interact with the DNA. These so-called epigenetic modifications are not transient, but persist through cell divisions. Rapidly advancing technologies, such as next-generation DNA sequencing, have dramatically increased our ability to survey epigenetic markers throughout an entire genome. These techniques are revealing in great detail that the many forms and stages of cancer are characterized by a massive number of epigenetic changes. Interpreting such epigenetic marks in cell differentiation and in carcinogenesis is computationally challenging. We review several examples of epigenetic data analysis and discuss the need for computational methods that will enable us to learn from the data the relationships between different kinds of histone modifications and DNA methylation.

The epigenetic marking of chromatin in the brain has recently been recognized as an essential mechanism for brain functions such as learning and memory formation. It allows nerve cells not only to respond to environmental stimuli and modulate their profile of gene expression, but also to establish and maintain their own identity. The epigenetic code is conferred by a set of covalent modifications on the basic elements of chromatin, DNA and histone proteins. These changes are catalyzed by specific enzymes and mechanisms, which include DNA methylation, and post-translational modifications of histone proteins such as acetylation, phosphorylation, methylation and ubiquitination. They are both stable and highly dynamic, and are triggered during stimulation of neuronal circuits but can also persist thereafter. Their study in animal models has demonstrated their importance, and revealed some of their modes of function.

The term epigenetic landscape was coined by CH Waddington to describe how cell fates were established in development, visualized as valleys and ridges directing the irreversibility of cell type differentiation. It is now clear that normal differentiation control breaks down during tumor development and that all tumor types show aberrant regulation of the epigenetic code, including changes in DNA methylation, histone modification and microRNAs. This has led to much interest in the development of epigenetic cancer therapies to target this aberrant epigenetic regulation. Histone deacetylase and DNA methyltransferase inhibitors are now used in the treatment of certain hematological malignancies. However, their more general applicability to solid tumors may be limited by lack of specificity and delivery challenges. Approaches to overcome these limitations and how to develop more specific drugs are discussed. The use of RNAi in the context of genome regulation as well as the possibility to use polyamides and engineered zinc fingers to target master regulators in the future is examined. Ultimately, improved specificity of epigenetic therapies will require increased mapping of the aberrant epigenetic landscape in cancer and cancer-specific target validation using chemical epigenetic approaches.

The eukaryotic DNA is wrapped around histone octamers, which consist of four different histones, H2A, H2B, H3 and H4. The N-terminal tail of each histone is post-transcriptionally modified. The modification patterns constitute codes that regulate chromatin organisation and DNA utilization processes, including transcription. Recent progress in technology development has made it possible to perform systematic genome-wide studies of histone modifications. This helps immensely in deciphering the histone codes and their biological influence. In this review, we discuss the histone modification patterns found in genome-wide studies in different biological models and how they influence cell differentiation and carcinogenesis.

After the completion of the human genome, a need was identified by scientists to look for a functional map of the human genome. Epigenomics provided functional characteristics of genes identified in the genome. Epigenetics is the alteration in gene expression (function) without changing the nucleotide sequence. Both activation and inactivation of cancer-associated genes can occur by epigenetic mechanisms. The major players in epigenetic mechanisms of gene regulation are DNA methylation, histone deacetylation, chromatin remodeling, small noncoding RNA expression and gene imprinting. In the last few years, epigenetic mechanisms have been studied in a number of tumor types and epigenetic markers have been identified that are suitable for cancer detection, diagnosis, follow-up of treatment and screening high-risk populations. One interesting aspect of epigenetics is the reactivation of genes by successful reversion of some epigenetic changes using chemicals. The reversibility of epigenetic aberrations has made them attractive targets for cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases, leading to the reactivation of silenced genes. In this article, we have described the current status of this powerful science and discussed the challenges in the clinical fields where epigenetic approaches in cancer are applied.

Enzymatic methylation of cytosine residues in DNA, in conjunction with covalent histone modifications, establishes an epigenetic code essential for the proper control of gene expression in higher organisms. Once established during cellular differentiation, the epigenetic code must be faithfully transmitted to progeny cells. However, epigenetic perturbations can be found in most if not all cancer cells, and the mechanisms leading to these changes are not well understood. In this paper, we describe a series of experiments aimed at understanding the dynamic process of DNA methylation that follows DNA replication. Cells in culture can be propagated in the presence of (15)N-enriched uridine, which labels the pyrimidine precursor pool as well as newly replicated DNA. Simultaneous culture in the presence of (2)H-enriched methionine results in labeling of newly methylated cytosine residues. An ensemble of 5-methylcytosine residues differing in the degree of isotopic enrichment is generated, which can be examined by mass spectrometry. Using this method, we demonstrate that the kinetics of both DNA replication and methylation of newly replicated DNA are indistinguishable. The majority of methylation following DNA replication is shown to occur on the newly synthesized DNA. The method reported here does, however, suggest an unexpected methylation of parental DNA during DNA replication, which might indicate a previously undescribed chromatin remodeling process. The method presented here will be useful in monitoring the dynamic process of DNA methylation and will allow a more detailed understanding of the mechanisms of clinically used methylation inhibitors and environmental toxicants.

Maintenance of alternative chromatin states through cell divisions pose some fundamental constraints on the dynamics of histone modifications. In this paper, we study the systems biology of epigenetic inheritance by defining and analyzing general classes of mathematical models. We discuss how the number of modification states involved plays an essential role in the stability of epigenetic states. In addition, DNA duplication and the consequent dilution of marked histones act as a large perturbation for a stable state of histone modifications. The requirement that this large perturbation falls into the basin of attraction of the original state sometimes leads to additional constraints on effective models. Two such models, inspired by two different biological systems, are compared in their fulfilling the requirements of multistability and of recovery after DNA duplication. We conclude that in the presence of multiple histone modifications that characterize alternative epigenetic stable states, these requirements are more easily fulfilled.