Types Of Histone Modifications Research Articles

An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions.

Epigenetic changes are changes in gene expression that do not involve alterations to the DNA sequence. These changes lead to establishing a so-called epigenetic code that dictates which and when genes are activated, thus orchestrating gene regulation and playing a central role in development, health, and disease. The brain, being mostly formed by cells that do not undergo a renewal process throughout life, is highly prone to the risk of alterations leading to neuronal death and neurodegenerative disorders, mainly at a late age. Here, we review the main epigenetic modifications that have been described in the brain, with particular attention on those related to the onset of developmental anomalies or neurodegenerative conditions and/or occurring in old age. DNA methylation and several types of histone modifications (acetylation, methylation, phosphorylation, ubiquitination, sumoylation, lactylation, and crotonylation) are major players in these processes. They are directly or indirectly involved in the onset of neurodegeneration in Alzheimer's or Parkinson's disease. Therefore, this review briefly describes the roles of these epigenetic changes in the mechanisms of brain development, maturation, and aging and some of the most important factors dynamically regulating or contributing to these changes, such as oxidative stress, inflammation, and mitochondrial dysfunction.

Histone acetylation dynamics in repair of DNA double-strand breaks.

Packaging of eukaryotic genome into chromatin is a major obstacle to cells encountering DNA damage caused by external or internal agents. For maintaining genomic integrity, the double-strand breaks (DSB) must be efficiently repaired, as these are the most deleterious type of DNA damage. The DNA breaks have to be detected in chromatin context, the DNA damage response (DDR) pathways have to be activated to repair breaks either by non‐ homologous end joining and homologous recombination repair. It is becoming clearer now that chromatin is not a mere hindrance to DDR, it plays active role in sensing, detection and repair of DNA damage. The repair of DSB is governed by the reorganization of the pre-existing chromatin, leading to recruitment of specific machineries, chromatin remodelling complexes, histone modifiers to bring about dynamic alterations in histone composition, nucleosome positioning, histone modifications. In response to DNA break, modulation of chromatin occurs via various mechanisms including post-translational modification of histones. DNA breaks induce many types of histone modifications, such as phosphorylation, acetylation, methylation and ubiquitylation on specific histone residues which are signal and context dependent. DNA break induced histone modifications have been reported to function in sensing the breaks, activating processing of breaks by specific pathways, and repairing damaged DNA to ensure integrity of the genome. Favourable environment for DSB repair is created by generating open and relaxed chromatin structure. Histone acetylation mediate de-condensation of chromatin and recruitment of DSB repair proteins to their site of action at the DSB to facilitate repair. In this review, we will discuss the current understanding on the critical role of histone acetylation in inducing changes both in chromatin organization and promoting recruitment of DSB repair proteins to sites of DNA damage. It consists of an overview of function and regulation of the deacetylase enzymes which remove these marks and the function of histone acetylation and regulators of acetylation in genome surveillance.

The critical role of histone modifications in lung adenocarcinoma based on novel molecular subtypes.

e20510 Background: Studies revealed the pathogenesis and exploring the treatment of lung adenocarcinoma (LUAD), but overall survival (OS) of LUAD patients still remains low in the recent years. Methods: This study analyzed the relationship between gene expression and histone modifications, and discussed the prognostic value of these findings in patients with LUAD. Four types of histone modifications including H3K9me3, H3K27me3, H3K27ac and H3K4me3 were included. Promoters and enhancers in protein coding genes (PCGs) were selected as targeted analyzing regions. Unsupervised consensus clustering was performed to identify molecular subtypes. Cox regression analysis and stepwise Akaike information criterion (stepAIC) were applied to construct a prognostic model. Results: A large number of epigenetic abnormal genes in lung adenocarcinoma were found by comparing the histone modifications and methylation regions on the elements including. We identified 699 epigenetic dysregulated genes specific to LUAD. Finally, based on these epi-PCGs, we constructed three molecular types of LUAD and identified 5 epi-PCGs as prognostic markers for LUAD patients. Conclusions: Our research provided a better understanding that the abnormal epigenetic regulation of PCG expression contributes a lot for the progress of gene regulation in LUAD. These novel molecular subtypes and the prognostic model could serve as guiders to assist decision-makings for LUAD treatment.

Integrated multi-omics reveal epigenomic disturbance of assisted reproductive technologies in human offspring.

BackgroundThe births of more than 8 million infants have been enabled globally through assisted reproductive technologies (ARTs), including conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with either fresh embryo transfer (ET) or frozen embryo transfer (FET). However, the safety issue regarding ARTs has drawn growing attention with accumulating observations of rising health risks, and underlying epigenetic mechanisms are largely uncharacterized.MethodsIn order to clarify epigenetic risks attributable to ARTs, we profiled DNA methylome on 137 umbilical cord blood (UCB) and 158 parental peripheral blood (PPB) samples, histone modifications (H3K4me3, H3K4me1, H3K27me3 and H3K27ac) on 33 UCB samples and transcriptome on 32 UCB samples by reduced representation bisulfite sequencing (RRBS), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA sequencing (RNA-seq), respectively.FindingsWe revealed that H3K4me3 was the most profoundly impacted by ICSI and freeze-thawing operation compared with the other three types of histone modifications. IVF-ET seemed to introduce less disturbance into infant epigenomes than IVF-FET or ICSI-ET did. ARTs also decreased the similarity of DNA methylome within twin pairs, and we confirmed that ART per se would introduce conservative changes locally through removal of parental effect. Importantly, those unique and common alterations induced by different ART procedures were highly enriched in the processes related to nervous system, cardiovascular system and glycolipid metabolism etc., which was in accordance with those findings in previous epidemiology studies and suggested some unexplored health issues, including in the immune system and skeletal system.InterpretationDifferent ART procedures can induce local and functional epigenetic abnormalities, especially for DNA methylation and H3K4me3, providing an epigenetic basis for the potential long-term health risks in ART-conceived offspring.Funding sourcesThis study was funded by National Natural Science Foundation of China (81,730,038; 81,521,002), National Key Research and Development Program (2018YFC1004000; 2017YFA0103801; 2017YFA0105001) and Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020703). Yang Wang was supported by Postdoctoral Fellowship of Peking-Tsinghua Center for Life Science.

ICGEC: a comparative method for measuring epigenetic conservation of genes via the integrated signal from multiple histone modifications between cell types

BackgroundHistone post-translational modifications play crucial roles in epigenetic regulation of gene expression and are known to be associated with the phenotypic differences of different cell types. Therefore, it is of fundamental importance to dissect the genes and pathways involved in such a phenotypic variation at the level of epigenetics. However, the existing comparative approaches are largely based on the differences, especially the absolute difference in the levels of individual histone modifications of genes under contrasting conditions. Thus, a method for measuring the overall change in the epigenetic circumstance of each gene underpinned by multiple types of histone modifications between cell types is lacking.ResultsTo address this challenge, we developed ICGEC, a new method for estimating the degree of epigenetic conservation of genes between two cell lines. Different from existing comparative methods, ICGEC provides a reliable score for measuring the relative change in the epigenetic context of corresponding gene between two conditions and simultaneously produces a score for each histone mark. The application of ICGEC to the human embryonic stem cell line H1 and four H1-derived cell lines with available epigenomic data for the same 16 types of histone modifications indicated high robustness and reliability of ICGEC. Furthermore, the analysis of the epigenetically dynamic and conserved genes which were defined based on the ICGEC output results demonstrated that ICGEC can deepen our understanding of the biological processes of cell differentiation to overcome the limitations of traditional expression analysis. Specifically, the ICGEC-derived differentiation-direction-specific genes were shown to have putative functions that are well-matched with cell identity. Additionally, H3K79me1 and H3K27ac were found to be the main histone marks accounting for whether an epigenetically dynamic gene was differentially expressed between two cell lines.ConclusionsThe use of ICGEC creates a convenient and robust way to measure the overall epigenetic conservation of individual genes and marks between two conditions. Thus, it provides a basis for exploring the epigenotype-phenotype relationship. ICGEC can be deemed a state-of-the-art method tailored for comparative epigenomic analysis of changes in cell dynamics.

Global epigenetic changes of histone modification under environmental stresses in rice root.

Abiotic stresses are non-living factors with negative morphological and physiological effects on living organisms. Substantial evidence exists that gene expression changes during plant cell growth are regulated by chromatin reconfiguration and histone modification. Several types of histone modifications are dramatically transformed in stress-responsive gene regions under drought stress conditions. Environmental stresses also cause the root apical meristem (RAM) region to decelerate root growth. In this study, we investigated how quantitative changes in epigenetic markers in this region influence rice morphology and physiology. Both iron and salinity treatments changed the epigenetic landscape from euchromatic to heterochromatic according to heterochromatin (H3K9me2) and euchromatin (H3K4me) markers, especially in the proximal meristem region. Moreover, supplementation with external abscisic acid (ABA) was able to mimic the effect of environmental stresses on global epigenetic changes. In contrast, the addition of external auxin (IAA) to rice under saline conditions affected heterochromatin formation without influencing euchromatin transformation. Chromatin dynamics is therefore believed to be directly connected to plant growth regulator signaling. We discuss insights into the role of plant growth regulators: ABA and IAA, peroxide signaling, and their effects on the global epigenetic change of histone modification under abiotic stresses.

Chromodomain Y-like Protein–Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors

BackgroundMajor depressive disorder is a prevalent and life-threatening illness in modern society. The susceptibility to major depressive disorder is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here, we examined the role of histone crotonylation, a novel type of histone modification, and chromodomain Y-like protein (CDYL), a crotonyl-coenzyme A hydratase and histone methyllysine reader, in this process. MethodsWe used chronic social defeat stress and microdefeat stress to examine the depressive behaviors. In addition, we combined procedures that diagnose behavioral strategy in male mice with histone extraction, viral-mediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification. ResultsThe results indicate that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex concurrent with selective upregulation of CDYL. Overexpression of CDYL in the prelimbic cortex, a subregion of the medial prefrontal cortex, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in the prelimbic cortex prevents chronic social defeat stress–induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF nerve growth factor inducible, and this activity is dependent on its dual effect on histone crotonylation and H3K27 trimethylation on the VGF promoter. ConclusionsOur results demonstrate that CDYL-mediated histone crotonylation plays a critical role in regulating stress-induced depression, providing a potential therapeutic target for major depressive disorder.

The genome-wide transcriptional regulatory landscape of ecdysone in the silkworm

BackgroundThe silkworm, Bombyx mori, a typical representative of metamorphic insects, is of great agricultural and economic importance. The steroid hormone ecdysone (20-hydroxyecdysone, 20E) is the central regulator of insect developmental transitions, and its nuclear receptors are crucial for numerous biological processes, including reproduction, metabolism, and immunity. However, genome-wide DNA regulatory elements and the ecdysone receptor (EcR) that control these programs of gene expression are not well defined.ResultsIn this study, we investigated the alterations in three types of histone modification in silkworm embryonic cells treated with 20E by chromatin immunoprecipitation sequencing (ChIP-seq). We identified enhancers using histone modifications and derived genome-wide ecdysone-dependent enhancer activity maps in the silkworm. We found enhancers enriched for monomethylation of histone H3 Lys4 (H3K4me1) that showed dynamic changes in acetylation of histone H3 Lys27 (H3K27ac) after 20E treatment and functioned to regulate the transcription of specific genes. EcR regulated transcription by binding not only to proximal promoters but also to the distal enhancers of target genes. Moreover, only 52.65% EcR peaks contained ecdysone response element (EcRE) motif, suggesting that EcR regulates the expression of target genes not only by binding directly to EcRE, but also by binding with other transcription factor.ConclusionsOur findings provide novel insights into the complex regulatory landscape of hormone-responsive cell activity and a basis for understanding the complex transcriptional regulatory processes of ecdysone.

Site-Specific Installation of Succinyl Lysine Analog into Histones Reveals the Effect of H2BK34 Succinylation on Nucleosome Dynamics

Posttranslational modifications of histones play key roles in the dynamic regulation of chromatin structure. Lysine succinylation is a new type of histone modification, but its biological significance in chromatin structure and dynamics remains unknown. Here we develop a chemical approach to site-specifically install a succinyl lysine analog into histones. This analog serves as an ideal structural and functional mimic to natural succinyl lysine. The incorporation of this succinylation mimic into histone H2B at lysine 34, a succinylation site at the nucleosomal DNA-histone interface, leads to significant decrease in nucleosome stability invitro, which is consistent with the defects in chromatin structure of a budding yeast strain containing a lysine-to-glutamate mutation at the corresponding residue of yeast histone H2B. This study provides a simple method for the rapid generation of histones with site-specific succinylation mimics, and reveals novel regulatory mechanisms of histone succinylation in the dynamic organization of chromatin.

Epigenetic memory effects in forest trees: a victory of “Michurinian biology”?

AbstractThe study reviews trait inheritance, which is in contradiction with the rules of Mendelian genetics, and which was object of controversies among biologists (sometimes with grave political consequences) in the USSR and Sovietcontrolled countries in the 1930s-1960s. “Carryover” or “memory” effects of the climate, to which maternal trees are exposed during seed development, on phenological behavior and other adaptively relevant traits of their offspring in conifers are mentioned; similar effects are associated with the germination and early growth environment. Molecular mechanisms underlying these effects include covalent modifications of DNA or DNA-associated proteins (cytosine methylation, various types of histone modifications), micro-RNAs and small interfering RNAs. Tools for the identification of these modifications are reviewed with a focus on cytosine methylation, along with an overview of the hitherto knowledge on the occurrence of DNA modifications in forest trees. The practical implications of epigenetic inheritance in forest trees are discussed with the focus on the adaptation to climate change and legislation on forest reproductive materials.

Use of Histone K-M Mutants for the Analysis of Transcriptional Regulation in Mouse Zygotes.

Histone modifications are dramatically altered during the pronuclear (PN) stage of zygotes, and more markedly in paternal than maternal pronuclei. Among various types of histone modifications, lysine methylation exhibits the most dynamic changes in the PN stage . To analyze the physiological functions of histone methylations, it is therefore important to elucidate the mechanism of epigenetic reprogramming. However, loss-of-function approaches using mutant histones whose lysine residues have been substituted with arginine residues are unable to erase histone modifications at all levels, since they are incapable of entirely replacing endogenous histones. To solve this problem, we used an alternative histone mutant whose lysine residues were substituted with methionine (K-M mutants). This mutant cannot be methylated itself but also prevents methylation of endogenous histones. We also developed a simple method for analyzing global transcription levels in early preimplantation embryos, involving using a commercial kit to examine the involvement of histone methylation in zygotic gene activation.

Identification of a novel Arabidopsis mutant showing sensitivity to histone deacetylase inhibitors

In the eukaryote nucleus, DNA wraps around histone cores and each core complex contains eight proteins including four pairs of H2A, H2B, H3, and H4 protein. The histone tail can be modified to alter the interaction strength between the histone core and a given DNA region, resulting in a change in gene expression. Various types of histone modifications are known to be involved in a number of cellular responses. In this study, we identified and characterized a novel mutant based on a growth assay using histone deacetylase inhibitors in combination with auxin, and we have named the mutant sensitive to histone deacetylase inhibitors 1. Our results imply that histone acetylation plays an important role in shoot morphology and leaf production in Arabidopsis.

Global Regulation of Plant Immunity by Histone Lysine Methyl Transferases.

Posttranslational modification of histones modulates gene expression affecting diverse biological functions. We showed that the Arabidopsis thaliana histone methyl transferases SET DOMAIN GROUP8 (SDG8) and SDG25 regulate pep1-, flg22-, and effector-triggered immunity as well as systemic acquired resistance. Genome-wide basal and induced transcriptome changes regulated by SDG8 and/or SDG25 showed that two genes of the SDG-dependent transcriptome, CAROTENOID ISOMERASE2 (CCR2) and ECERIFERUM3 (CER3), were also required for plant immunity, establishing mechanisms in defense functions for SDG8 and SDG25. CCR2 catalyzes the biosynthesis of carotenoids, whereas CER3 is involved in the biosynthesis of cuticular wax. SDG8 and SDG25 affected distinct and overlapping global and locus-specific histone H3 lysine 4 (H3K4) and histone H3 lysine 36 (H3K36) methylations. Loss of immunity in sdg mutants was attributed to altered global and CCR2- and CER3-specific histone lysine methylation (HLM). Loss of immunity in sdg, ccr2, and cer3 mutants was also associated with diminished accumulation of lipids and loss of cuticle integrity. In addition, sdg8 and sdg25 mutants were impaired in H2B ubiquitination (H2Bubn) at CCR2, CER3, and H2Bubn regulated R gene, SNC1, revealing crosstalk between the two types of histone modifications. In summary, SDG8 and SDG25 contribute to plant immunity directly through HLM or indirectly through H2Bubn and by regulating expression of plant immunity genes, accumulation of lipids, biosynthesis of carotenoids, and maintenance of cuticle integrity.

Identification of Epigenetic Biomarkers of Lung Adenocarcinoma through Multi-Omics Data Analysis.

Epigenetic mechanisms such as DNA methylation or histone modifications are essential for the regulation of gene expression and development of tissues. Alteration of epigenetic modifications can be used as an epigenetic biomarker for diagnosis and as promising targets for epigenetic therapy. A recent study explored cancer-cell specific epigenetic biomarkers by examining different types of epigenetic modifications simultaneously. However, it was based on microarrays and reported biomarkers that were also present in normal cells at a low frequency. Here, we first analyzed multi-omics data (including ChIP-Seq data of six types of histone modifications: H3K27ac, H3K4me1, H3K9me3, H3K36me3, H3K27me3, and H3K4me3) obtained from 26 lung adenocarcinoma cell lines and a normal cell line. We identified six genes with both H3K27ac and H3K4me3 histone modifications in their promoter regions, which were not present in the normal cell line, but present in ≥85% (22 out of 26) and ≤96% (25 out of 26) of the lung adenocarcinoma cell lines. Of these genes, NUP210 (encoding a main component of the nuclear pore complex) was the only gene in which the two modifications were not detected in another normal cell line. RNA-Seq analysis revealed that NUP210 was aberrantly overexpressed among the 26 lung adenocarcinoma cell lines, although the frequency of NUP210 overexpression was lower (19.3%) in 57 lung adenocarcinoma tissue samples studied and stored in another database. This study provides a basis to discover epigenetic biomarkers highly specific to a certain cancer, based on multi-omics data at the cell population level.

Histone modifications involved in cassette exon inclusions: a quantitative and interpretable analysis.

BackgroundChromatin structure and epigenetic modifications have been shown to involve in the co-transcriptional splicing of RNA precursors. In particular, some studies have suggested that some types of histone modifications (HMs) may participate in the alternative splicing and function as exon marks. However, most existing studies pay attention to the qualitative relationship between epigenetic modifications and exon inclusion. The quantitative analysis that reveals to what extent each type of epigenetic modification is responsible for exon inclusion is very helpful for us to understand the splicing process.ResultsIn this paper, we focus on the quantitative analysis of HMs’ influence on the inclusion of cassette exons (CEs) into mature RNAs. With the high-throughput ChIP-seq and RNA-seq data obtained from ENCODE website, we modeled the association of HMs with CE inclusions by logistic regression whose coefficients are meaningful and interpretable for us to reveal the effect of each type of HM. Three type of HMs, H3K36me3, H3K9me3 and H4K20me1, were found to play major role in CE inclusions. HMs’ effect on CE inclusions is conservative across cell types, and does not depend on the expression levels of the genes hosting CEs. HMs located in the flanking regions of CEs were also taken into account in our analysis, and HMs within bounded flanking regions were shown to affect moderately CE inclusions. Moreover, we also found that HMs on CEs whose length is approximately close to nucleosomal-DNA length affect greatly on CE inclusion.ConclusionsWe suggested that a few types of HMs correlate closely to alternative splicing and perhaps function jointly with splicing machinery to regulate the inclusion level of exons. Our findings are helpful to understand HMs’ effect on exon definition, as well as the mechanism of co-transcriptional splicing.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-1148) contains supplementary material, which is available to authorized users.

Comparative epigenetic analyses reveal distinct patterns of oncogenic pathways activation in breast cancer subtypes

Breast cancer is a highly heterogeneous disease that is characterized by genetic and epigenetic aberrations; however, our knowledge of epigenetic alterations of breast cancer subtypes remains limited. Here, we portrayed and compared the alterations of six types of histone modifications and DNA methylation between two breast cancer subtypes, luminal and basal. Widespread subtype-specific epigenetic alterations were observed in both subtypes, which preferentially occurred within CpG islands (CGIs) and promoter regions. Specifically, aberrant DNA methylation was mostly located inside CGIs in luminal subtype, whereas in basal subtype it was principally located within CGI shores. Moreover, different types and combinatorial patterns of epigenetic alterations were found to occupy at promoter regions between these two subtypes. And these epigenetic alterations regulated corresponding gene expression in a synergetic way in both subtypes. Functional enrichment analysis highlighted that epigenetically dysregulated genes were significantly involved in the hallmarks of cancers, most of which were subtype specific. Even genes involved in the same hallmarks associated biological processes were affected by various types of epi-modifications in different subtypes. Finally, we revealed distinct patterns of oncogenic pathways activation in different subtypes and provided novel insights into subtype specific therapeutic opportunities. In addition, genes in the key signaling pathways were able to discriminate between disease phenotypes, and subtype-specific progression associated genes were identified. This study presents the aberrant epigenetic patterns of breast cancer subtypes at a genome-wide level, which will be a highly valuable resource for investigations at understanding epigenetic regulation of breast cancer subtypes.

H3K4me2 reliably defines transcription factor binding regions in different cells

Histone modification (HM) patterns are widely applied to identify transcription factor binding regions (TFBRs). However, how frequently the TFBRs overlap with genomic regions enriched with certain types of HMs and which HM marker is more effective to pinpoint the TFBRs have not been systematically investigated. To address these problems, we studied 149 transcription factor (TF) ChIP-seq datasets and 33 HM ChIP-seq datasets in three cell lines. We found that on average about 90% of the TFBRs overlap with the H3K4me2-enriched regions. Moreover, the H3K4me2-enriched regions with stronger signals of H3K4me2 enrichment more likely overlap with the TFBRs than those with weaker signals. In addition, we showed that the H3K4me2-enriched regions together with the H3K27ac-enriched regions can greatly reduce false positive predictions of the TFBRs. Our study sheds light on the comprehensive discovery of the TFBRs using the HeK4me-enriched regions, especially when no good antibody to a TF exists.

Patterns of chromatin-modifications discriminate different genomic features in Arabidopsis

Dynamic regulation and packaging of genetic information is achieved by the organization of DNA into chromatin. Nucleosomal core histones, which form the basic repeating unit of chromatin, are subject to various post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitinylation. These modifications have effects on chromatin structure and, along with DNA methylation, regulate gene transcription. The goal of this study was to determine if patterns in modifications were related to different categories of genomic features, and, if so, if the patterns had predictive value. In this study, we used publically available data (ChIP-chip) for different types of histone modifications (methylation and acetylation) and for DNA methylation for Arabidopsis thaliana and then applied a machine learning based approach (a support vector machine) to demonstrate that patterns of these modifications are very different among different kinds of genomic feature categories (protein, RNA, pseudogene, and transposon elements). These patterns can be used to distinguish the types of genomic features. DNA methylation and H3K4me3 methylation emerged as features with most discriminative power. From our analysis on Arabidopsis, we were able to predict 33 novel genomic features, whose existence was also supported by analysis of RNA-seq experiments. In summary, we present a novel approach which can be used to discriminate/detect different categories of genomic features based upon their patterns of chromatin modification and DNA methylation.

Nutritional epigenomics: a portal to disease prevention.

Epigenetics can be defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base pair sequence. Epigenomics is the study of genome-wide epigenetic modifications. Because gene expression changes are critical in both normal development and disease progression, epigenetics is widely applicable to many aspects of biological research. The influences of nutrients and bioactive food components on epigenetic phenomena such as DNA methylation and various types of histone modifications have been extensively investigated. Because an individual's epigenetic patterns are established during early gestation and are changed and personalized by environmental factors during our lifetime, epigenetic mechanisms are quite important in the development of transgenerational and adult obesity as well as in the development of diabetes mellitus. Aging and cancer demonstrate profound genome-wide DNA methylation changes, suggesting that nutrition may affect the aging process and cancer development through epigenetic mechanisms.

A Bayesian Graphical Model for ChIP-Seq Data on Histone Modifications

Histone modifications (HMs) are an important post-translational feature. Different types of HMs are believed to co-exist and co-regulate biological processes such as gene expression and, therefore, are intrinsically dependent on each other. We develop inference for this complex biological network of HMs based on a graphical model using ChIP-Seq data. A critical computational hurdle in the inference for the proposed graphical model is the evaluation of a normalization constant in an autologistic model that builds on the graphical model. We tackle the problem by Monte Carlo evaluation of ratios of normalization constants. We carry out a set of simulations to validate the proposed approach and to compare it with a standard approach using Bayesian networks. We report inference on HM dependence in a case study with ChIP-Seq data from a next generation sequencing experiment. An important feature of our approach is that we can report coherent probabilities and estimates related to any event or parameter of interest, including honest uncertainties. Posterior inference is obtained from a joint probability model on latent indicators for the recorded HMs. We illustrate this in the motivating case study. An R package including an implementation of posterior simulation in C is available from Riten Mitra upon request.