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1.  Human-specific epigenetic variation in the immunological Leukotriene B4 Receptor (LTB4R/BLT1) implicated in common inflammatory diseases 
Genome Medicine  2014;6(3):19.
Background
Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. Due to the environment’s influence on the epigenome, and therefore genome function, as well as conversely the genome’s facilitative effect on the epigenome, analysis of this level of regulation may increase our knowledge of disease pathogenesis.
Methods
In order to identify human-specific epigenetic influences, we have performed a novel genome-wide DNA methylation analysis comparing human, chimpanzee and rhesus macaque.
Results
We have identified that the immunological Leukotriene B4 receptor (LTB4R, BLT1 receptor) is the most epigenetically divergent human gene in peripheral blood in comparison with other primates. This difference is due to the co-ordinated active state of human-specific hypomethylation in the promoter and human-specific increased gene body methylation. This gene is significant in innate immunity and the LTB4/LTB4R pathway is involved in the pathogenesis of the spectrum of human inflammatory diseases. This finding was confirmed by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Additionally we show through functional analysis that this receptor has increased expression and a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. Genome-wide we also find human species-specific differentially methylated regions (human s-DMRs) are more prevalent in CpG island shores than within the islands themselves, and within the latter are associated with the CTCF motif.
Conclusions
This result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from very closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness.
doi:10.1186/gm536
PMCID: PMC4062055  PMID: 24598577
2.  Twins for epigenetic studies of human aging and development 
Ageing research reviews  2012;12(1):182-187.
Most of the complex traits including aging phenotypes are caused by the interaction between genome and environmental conditions and the interface of epigenetics may be a central mechanism. Although modern technologies allow us high-throughput profiling of epigenetic patterns already at genome level, our understanding of genetic and environmental influences on the epigenetic processes remains limited. Twins are of special interest for genetic studies due to their genetic similarity and rearing-environment sharing. The classical twin design has made a great contribution in dissecting the genetic and environmental contributions to human diseases and complex traits. In the era of functional genomics, the valuable sample of twins is helping to bridge the gap between gene activity and the environments through epigenetic mechanisms unlimited by DNA sequence variations. We propose toextend the classical twin design to studythe aging–related molecular epigenetic phenotypes and link them with environmental exposures especially early life events. Different study designs and application issues will be highlighted and novel approaches introduced with aim at making uses of twins in assessing the environmental impact on epigenetic changes during development and in the aging process.
doi:10.1016/j.arr.2012.06.004
PMCID: PMC3509237  PMID: 22750314
twins; aging; epigenetics; environments; genomics
3.  Epigenomic strategies at the interface of genetic and environmental risk factors for autism 
Journal of human genetics  2013;58(7):396-401.
Autism spectrum disorders have been increasing in prevalence over the past two decades, primarily because of increased awareness and diagnosis. However, autism is clearly a complex human genetic disorder that involves interactions between genes and environment. Epigenetic mechanisms such as DNA methylation act at the interface of genetic and environmental risk and protective factors. Advancements in genome-wide sequencing has broadened the view of the human methylome and revealed the organization of the human genome into large-scale methylation domains that footprint over neurologically important genes involved in embryonic development. Future integrative epigenomic analyses of genetic risk factors with environmental exposures and methylome analyses are expected to be important for understanding the complex etiology of autism spectrum disorders.
doi:10.1038/jhg.2013.49
PMCID: PMC3955092  PMID: 23677056
4.  Epigenome Mapping in Normal and Disease States 
Circulation research  2010;107(3):327-339.
Epigenomes are comprised, in part, of all genome-wide chromatin modifications including DNA methylation and histone modifications. Unlike the genome, epigenomes are dynamic during development and differentiation in order to establish and maintain cell type-specific gene expression states that underlie cellular identity and function. Chromatin modifications are particularly labile, providing a mechanism for organisms to respond and adapt to environmental cues. Results from studies in animal models clearly demonstrate that epigenomic variability leads to phenotypic variability including susceptibility to disease that is not recognized at the DNA sequence level. Thus, capturing epigenomic information is invaluable for comprehensively understanding development, differentiation, and disease. Herein, we provide a brief overview of epigenetic processes, how they are relevant to human health, and review studies utilizing technologies that enable epigenome mapping. We conclude by describing feasible applications of epigenome mapping, focusing on epigenome-wide association studies (eGWAS), which have the potential to revolutionize current studies of human diseases and will likely promote the discovery of novel diagnostic, preventative, and treatment strategies.
doi:10.1161/CIRCRESAHA.110.222463
PMCID: PMC2917837  PMID: 20689072
Epigenetics; genetics; gene expression; gene regulation
5.  Fine Tuning Gene Expression: The Epigenome 
Seminars in nephrology  2010;30(5):468-476.
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 epigenetic marks under environmental influence, 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.
doi:10.1016/j.semnephrol.2010.07.004
PMCID: PMC3164355  PMID: 21044758
6.  Timing is everything 
Epigenetics  2011;6(7):791-797.
Environmental influence on developmental plasticity impacts a wide diversity of animal life from insects to humans. We now understand the epigenetic basis for many of these altered phenotypes. The five environmental factors of nutrition, behavior, stress, toxins and stochasticity work individually and in concert to affect the developing epigenome. During early embryogenesis, epigenetic marks, such as DNA methylation, are reset at specific times. Two waves of global demethylation and reestablishment of methylation frame the sensitive times for early environmental influences and will be the focus of this review. Gene transcription, translation and post-translational modification of chromatin remodeling complexes are three mechanisms affected by developmental exposure to environmental factors. To illustrate how changes in the early environment profoundly affect these mechanisms, we provide examples throughout the animal kingdom. Herein we review the history, time points and mechanisms of epigenetic gene-environment interaction.
doi:10.4161/epi.6.7.16209
PMCID: PMC3230539  PMID: 21636976
epigenetics; development; environment; DNA methylation; plasticity; environmental epigenomics
7.  Epigenomics of Hypertension 
Seminars in nephrology  2013;33(4):392-399.
Multiple genes and pathways are involved in the pathogenesis of hypertension. Epigenomic studies of hypertension are beginning to emerge and hold great promise of providing novel insights into the mechanisms underlying hypertension. Epigenetic marks or mediators including DNA methylation, histone modifications, and non-coding RNA can be studied at a genome or near-genome scale using epigenomic approaches. At the single gene level, several studies have identified changes in epigenetic modifications in genes expressed in the kidney that correlate with the development of hypertension. Systematic analysis and integration of epigenetic marks at the genome scale, demonstration of cellular and physiological roles of specific epigenetic modifications, and investigation of inheritance are among the major challenges and opportunities for future epigenomic and epigenetic studies of hypertension.
Essential hypertension is a multifactorial disease involving multiple genetic and environmental factors and mediated by alterations in multiple biological pathways. Because the non-genetic mechanisms may involve epigenetic modifications, epigenomics is one of the latest concepts and approaches brought to bear on hypertension research. In this article, we summarize briefly the concepts and techniques for epigenomics, discuss the rationale for applying epigenomic approaches to study hypertension, and review the current state of this research area.
doi:10.1016/j.semnephrol.2013.05.011
PMCID: PMC3777799  PMID: 24011581
8.  Epigenomics of cancer – emerging new concepts 
Biochimie  2012;94(11):2219-2230.
The complexity of the mammalian genome is regulated by heritable epigenetic mechanisms, which provide the basis for differentiation, development and cellular homeostasis. These mechanisms act on the level of chromatin, by modifying DNA, histone proteins and nucleosome density/composition. During the last decade it became clear that cancer is defined by a variety of epigenetic changes, which occur in early stages of disease and parallel genetic mutations. With the advent of new technologies we are just starting to unravel the cancer epigenome and latest mechanistic findings provide the first clue as to how altered epigenetic patterns might occur in different cancers. Here we review latest findings on chromatin related mechanisms and hypothesize how their impairment might contribute to the altered epigenome of cancer cells.
Highlights
► Genome-wide analyses reveal epigenomic differences in functional regions. ► Epigenetic patterns occur in large domains in the genome. ► Epigenetic mechanisms are interrelated. ► Mutations of epigenetic enzymes are frequently associated with cancer. ► Changes in nuclear architecture are related to epigenomic alterations in cancer.
doi:10.1016/j.biochi.2012.05.007
PMCID: PMC3480634  PMID: 22609632
Cancer epigenetics; Chromatin; Nuclear architecture; DNA methylation; Histone modification; lncRNA
9.  Why is epigenetics important in understanding the pathogenesis of inflammatory musculoskeletal diseases? 
In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifications and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifiers reveal the importance of epigenomic mechanisms in human pathologies, including inflammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in inflammatory and autoimmune diseases.
doi:10.1186/ar4186
PMCID: PMC3672786  PMID: 23566317
10.  Gene–Lifestyle Interactions in Obesity 
Current Nutrition Reports  2012;1:184-196.
Obesity is a complex multifaceted disease resulting from interactions between genetics and lifestyle. The proportion of phenotypic variance ascribed to genetic variance is 0.4 to 0.7 for obesity and recent years have seen considerable success in identifying disease-susceptibility variants. Although with the advent of genome-wide association studies the list of genetic variants predisposing to obesity has significantly increased the identified variants only explain a fraction of disease heritability. Studies of gene–environment interactions can provide more insight into the biological mechanisms involved in obesity despite the challenges associated with such designs. Epigenetic changes that affect gene function without DNA sequence modifications may be a key factor explaining interindividual differences in obesity, with both genetic and environmental factors influencing the epigenome. Disentangling the relative contributions of genetic, environmental and epigenetic marks to the establishment of obesity is a major challenge given the complex interplay between these determinants.
doi:10.1007/s13668-012-0022-2
PMCID: PMC3873060  PMID: 24392269
Gene–environment interaction; Lifestyle; Genetics; Environment; Epigenetics; Obesity; Epigenome
11.  DNA Methylation, Epigenetics, and Evolution in Vertebrates: Facts and Challenges 
DNA methylation is a key epigenetic modification in the vertebrate genomes known to be involved in biological processes such as regulation of gene expression, DNA structure and control of transposable elements. Despite increasing knowledge about DNA methylation, we still lack a complete understanding of its specific functions and correlation with environment and gene expression in diverse organisms. To understand how global DNA methylation levels changed under environmental influence during vertebrate evolution, we analyzed its distribution pattern along the whole genome in mammals, reptiles and fishes showing that it is correlated with temperature, independently on phylogenetic inheritance. Other studies in mammals and plants have evidenced that environmental stimuli can promote epigenetic changes that, in turn, might generate localized changes in DNA sequence resulting in phenotypic effects. All these observations suggest that environment can affect the epigenome of vertebrates by generating hugely different methylation patterns that could, possibly, reflect in phenotypic differences. We are at the first steps towards the understanding of mechanisms that underlie the role of environment in molding the entire genome over evolutionary times. The next challenge will be to map similarities and differences of DNA methylation in vertebrates and to associate them with environmental adaptation and evolution.
doi:10.1155/2014/475981
PMCID: PMC3914449  PMID: 24551476
12.  The Decade of the Epigenomes? 
Genes & Cancer  2011;2(6):680-687.
The beginning of this century was not only marked by the publication of the first draft of the human genome but also set off a decade of intense research on epigenetic phenomena. Apart from DNA methylation, it became clear that many other factors including a wide range of histone modifications, different shades of chromatin accessibility, and a vast suite of noncoding RNAs comprise the epigenome. With the recent advances in sequencing technologies, it has now become possible to analyze many of these features in depth, allowing for the first time the establishment of complete epigenomic profiles for basically every cell type of interest. Here, we will discuss the recent advances that allow comprehensive epigenetic mapping, highlight several projects that set out to better understand the epigenome, and discuss the impact that epigenomic mapping can have on our understanding of both healthy and diseased cells.
doi:10.1177/1947601911417860
PMCID: PMC3174262  PMID: 21941622
epigenome; chromatin accessibility; DNA methylation; ChIP-seq; RNA-seq
13.  A genomic point-of-view on environmental factors influencing the human brain methylome 
Epigenetics  2011;6(7):862-869.
The etiologic paradigm of complex human disorders such as autism is that genetic and environmental risk factors are independent and additive, but the interactive effects at the epigenetic interface are largely ignored. Genomic technologies have radically changed perspective on the human genome and how the epigenetic interface may impact complex human disorders. Here, I review recent genomic, environmental and epigenetic findings that suggest a new paradigm of “integrative genomics” in which genetic variation in genomic size may be impacted by dietary and environmental factors that influence the genomic saturation of DNA methylation. Human genomes are highly repetitive, but the interface of large-scale genomic differences with environmental factors that alter the DNA methylome such as dietary folate is under-explored. In addition to obvious direct effects of some environmental toxins on the genome by causing chromosomal breaks, non-mutagenic toxin exposures correlate with DNA hypomethylation that can lead to rearrangements between repeats or increased retrotransposition. Since human neurodevelopment appears to be particularly sensitive to alterations in epigenetic pathways, a further focus will be on how developing neurons may be particularly impacted by even subtle alterations to DNA methylation and proposing new directions towards understanding the quixotic etiology of autism by integrative genomic approaches.
doi:10.4161/epi.6.7.16353
PMCID: PMC3154427  PMID: 21617367
DNA methylation; copy number variation; autism; neurodevelopment; genomics; epigenomics; epigenetics; folate; folic acid; environmental exposures; Alu; MeCP2; LINE-1
14.  Epigenomics: The science of no-longer-“junk” DNA. Why study it in chronic kidney disease? 
Seminars in nephrology  2013;33(4):10.1016/j.semnephrol.2013.05.007.
Epigenetics refers to functionally relevant modifications of the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are DNA methylation and histone modifications. Both modifications serve to regulate gene expression without altering the underlying DNA sequence. The epigenome encodes critical information to regulate gene expression. The cellular epigenome is established during development and differentiation and maintained during cell division. These instructions are different in each cell type; therefore the epigenome is cell type specific. Nutrient availability and other environmental factors cause changes in the epigenome. Recent research suggests the critical contribution of the epigenome to the development of complex gene-environmental diseases including chronic kidney diseases.
doi:10.1016/j.semnephrol.2013.05.007
PMCID: PMC3815533  PMID: 24011577
15.  Next Generation Sequencing: Advances in Characterizing the Methylome  
Genes  2010;1(2):143-165.
Epigenetic modifications play an important role in lymphoid malignancies. This has been evidenced by the large body of work published using microarray technologies to generate methylation profiles for numerous types and subtypes of lymphoma and leukemia. These studies have shown the importance of defining the epigenome so that we can better understand the biology of lymphoma. Recent advances in DNA sequencing technology have transformed the landscape of epigenomic analysis as we now have the ability to characterize the genome-wide distribution of chromatin modifications and DNA methylation using next-generation sequencing. To take full advantage of the throughput of next-generation sequencing, there are many methodologies that have been developed and many more that are currently being developed. Choosing the appropriate methodology is fundamental to the outcome of next-generation sequencing studies. In this review, published technologies and methodologies applicable to studying the methylome are presented. In addition, progress towards defining the methylome in lymphoma is discussed and prospective directions that have been made possible as a result of next-generation sequencing technology. Finally, methodologies are introduced that have not yet been published but that are being explored in the pursuit of defining the lymphoma methylome.
doi:10.3390/genes1010143
PMCID: PMC3954092  PMID: 24710039
lymphoma; leukemia; next-generation sequencing; methylation; epigenome
16.  NCBI Epigenomics: a new public resource for exploring epigenomic data sets 
Nucleic Acids Research  2010;39(Database issue):D908-D912.
The Epigenomics database at the National Center for Biotechnology Information (NCBI) is a new resource that has been created to serve as a comprehensive public resource for whole-genome epigenetic data sets (www.ncbi.nlm.nih.gov/epigenomics). Epigenetics is the study of stable and heritable changes in gene expression that occur independently of the primary DNA sequence. Epigenetic mechanisms include post-translational modifications of histones, DNA methylation, chromatin conformation and non-coding RNAs. It has been observed that misregulation of epigenetic processes has been associated with human disease. We have constructed the new resource by selecting the subset of epigenetics-specific data from general-purpose archives, such as the Gene Expression Omnibus, and Sequence Read Archives, and then subjecting them to further review, annotation and reorganization. Raw data is processed and mapped to genomic coordinates to generate ‘tracks’ that are a visual representation of the data. These data tracks can be viewed using popular genome browsers or downloaded for local analysis. The Epigenomics resource also provides the user with a unique interface that allows for intuitive browsing and searching of data sets based on biological attributes. Currently, there are 69 studies, 337 samples and over 1100 data tracks from five well-studied species that are viewable and downloadable in Epigenomics.
doi:10.1093/nar/gkq1146
PMCID: PMC3013719  PMID: 21075792
17.  Single Molecule Epigenetic Analysis in a Nanofluidic Channel 
Analytical chemistry  2010;82(6):2480-2487.
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.
doi:10.1021/ac9028642
PMCID: PMC2839087  PMID: 20184350
Single-molecule; chromatin; epigenetics; epigenomics; DNA methylation; nanofluidics; laser-induced fluorescence; methyl binding domain protein; green fluorescent protein; HeLa cell
18.  Natural Single-Nucleosome Epi-Polymorphisms in Yeast 
PLoS Genetics  2010;6(4):e1000913.
Epigenomes commonly refer to the sequence of presence/absence of specific epigenetic marks along eukaryotic chromatin. Complete histone-borne epigenomes have now been described at single-nucleosome resolution from various organisms, tissues, developmental stages, or diseases, yet their intra-species natural variation has never been investigated. We describe here that the epigenomic sequence of histone H3 acetylation at Lysine 14 (H3K14ac) differs greatly between two unrelated strains of the yeast Saccharomyces cerevisiae. Using single-nucleosome chromatin immunoprecipitation and mapping, we interrogated 58,694 nucleosomes and found that 5,442 of them differed in their level of H3K14 acetylation, at a false discovery rate (FDR) of 0.0001. These Single Nucleosome Epi-Polymorphisms (SNEPs) were enriched at regulatory sites and conserved non-coding DNA sequences. Surprisingly, higher acetylation in one strain did not imply higher expression of the relevant gene. However, SNEPs were enriched in genes of high transcriptional variability and one SNEP was associated with the strength of gene activation upon stimulation. Our observations suggest a high level of inter-individual epigenomic variation in natural populations, with essential questions on the origin of this diversity and its relevance to gene x environment interactions.
Author Summary
Nucleosomes are the basic units of chromatin, with part of the long DNA molecule wrapped around a multiprotein core, which makes unpacked chromatin often portrayed as a string of pearls. This string can carry three types of sequences: DNA, methyl groups on cytosines, and, on every pearl, the presence-or-absence of histone post-translational modifications such as acetylation of lysines (nucleosomal epigenome). These latter sequences can change dynamically, and the mechanisms involved are heavily studied as they participate in many physiological processes (pluripotency, disease…). However, nothing is known about the natural diversity of nucleosomal epigenomes in natural populations. As a model, we compared two unrelated yeast strains for their epigenome of one histone modification. We found a high divergence, which was enriched at regulatory sites and often carried on specific nucleosomes. Although this nucleosome modification is usually associated with high transcription, higher acetylation in one strain did not necessarily imply higher expression of the corresponding gene. However, one nucleosomal variation was associated with a stronger gene activation upon stimulation. These results suggest that nucleosomal epigenomes largely differ between individuals, raising essential questions on the origin of these differences and their contribution to personal responses to environmental changes (such as clinical treatments).
doi:10.1371/journal.pgen.1000913
PMCID: PMC2858693  PMID: 20421933
19.  Emerging patterns of epigenomic variation 
Trends in genetics : TIG  2011;27(6):242-250.
Fuelled by new sequencing technologies, epigenome mapping projects are revealing epigenomic variation at all levels of biological complexity, from species to cells. Comparisons of methylation profiles among species reveal evolutionary conservation of gene body methylation patterns, pointing to the fundamental role of epigenomes in gene regulation. At the human population level, epigenomic changes provide footprints of the effects of genomic variants within the vast non-protein coding fraction of the genome while comparisons of the epigenomes of parents and their offspring point to quantitative epigenomic parent-of-origin effects confounding classical Mendelian genetics. At the organismal level, comparisons of epigenomes from diverse cell types provide insights into cellular differentiation. Finally, comparisons of epigenomes from monozygotic twins help dissect genetic and environmental influences on human phenotypes and longitudinal comparisons reveal aging-associated epigenomic drift. The development of new bioinformatic frameworks for comparative epigenome analysis is putting epigenome maps within reach of researchers across a wide spectrum of biological disciplines.
doi:10.1016/j.tig.2011.03.001
PMCID: PMC3104125  PMID: 21507501
20.  Basic concepts of epigenetics 
Epigenetics  2012;7(2):119-130.
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.
doi:10.4161/epi.7.2.18764
PMCID: PMC3335905  PMID: 22395460
DNA methyltransferases; methyl-CpG-binding proteins; H2A.Z; high mobility group proteins; SWI-SNF; nucleosomal remodeling complexes; heterochromatin proteins; epigenetics
21.  Epigenetic Contributions to the Relationship between Cancer and Dietary Intake of Nutrients, Bioactive Food Components, and Environmental Toxicants 
Epigenetics is the study of heritable changes in gene expression that occur without a change in DNA sequence. Cancer is a multistep process derived from combinational crosstalk between genetic alterations and epigenetic influences through various environmental factors. The observation that epigenetic changes are reversible makes them an attractive target for cancer prevention. Until recently, there have been difficulties studying epigenetic mechanisms in interactions between dietary factors and environmental toxicants. The development of the field of cancer epigenetics during the past decade has been advanced rapidly by genome-wide technologies – which initially employed microarrays but increasingly are using high-throughput sequencing – which helped to improve the quality of the analysis, increase the capacity of sample throughput, and reduce the cost of assays. It is particularly true for applications of cancer epigenetics in epidemiologic studies that examine the relationship among diet, epigenetics, and cancer because of the issues of tissue heterogeneity, the often limiting amount of DNA samples, and the significant cost of the analyses. This review offers an overview of the state of the science in nutrition, environmental toxicants, epigenetics, and cancer to stimulate further exploration of this important and developing area of science. Additional epidemiologic research is needed to clarify the relationship between these complex epigenetic mechanisms and cancer.
doi:10.3389/fgene.2011.00091
PMCID: PMC3266615  PMID: 22303385
cancer; epigenetics; diet; nutrient; toxicants
22.  IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype 
Nature  2012;483(7390):479-483.
Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology1–3. Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.
doi:10.1038/nature10866
PMCID: PMC3351699  PMID: 22343889
23.  Interplay between Epigenetics and Genetics in Cancer 
Genomics & Informatics  2013;11(4):164-173.
Genomic instability, which occurs through both genetic mechanisms (underlying inheritable phenotypic variations caused by DNA sequence-dependent alterations, such as mutation, deletion, insertion, inversion, translocation, and chromosomal aneuploidy) and epigenomic aberrations (underlying inheritable phenotypic variations caused by DNA sequence-independent alterations caused by a change of chromatin structure, such as DNA methylation and histone modifications), is known to promote tumorigenesis and tumor progression. Mechanisms involve both genomic instability and epigenomic aberrations that lose or gain the function of genes that impinge on tumor suppression/prevention or oncogenesis. Growing evidence points to an epigenome-wide disruption that involves large-scale DNA hypomethylation but specific hypermethylation of tumor suppressor genes, large blocks of aberrant histone modifications, and abnormal miRNA expression profile. Emerging molecular details regarding the modulation of these epigenetic events in cancer are used to illustrate the alterations of epigenetic molecules, and their consequent malfunctions could contribute to cancer biology. More recently, intriguing evidence supporting that genetic and epigenetic mechanisms are not separate events in cancer has been emerging; they intertwine and take advantage of each other during tumorigenesis. In addition, we discuss the collusion between epigenetics and genetics mediated by heterochromatin protein 1, a major component of heterochromatin, in order to maintain genome integrity.
doi:10.5808/GI.2013.11.4.164
PMCID: PMC3897842  PMID: 24465226
epigenomics; genetics; heterochromatin-specific nonhistone chromosomal protein HP-1; neoplasms
24.  The epigenome and top-down causation 
Interface Focus  2011;2(1):42-48.
Genes store heritable information, but actual gene expression often depends on many so-called epigenetic factors, both physical and chemical, external to DNA. Epigenetic changes can be both reversible and heritable. The genome is associated with a physical object (DNA) with a specific location, whereas the epigenome is a global, systemic, entity. Furthermore, genomic information is tied to specific coded molecular sequences stored in DNA. Although epigenomic information can be associated with certain non-DNA molecular sequences, it is mostly not. Therefore, there does not seem to be a stored ‘epigenetic programme’ in the information-theoretic sense. Instead, epigenomic control is—to a large extent—an emergent self-organizing phenomenon, and the real-time operation of the epigenetic ‘project’ lies in the realm of nonlinear bifurcations, interlocking feedback loops, distributed networks, top-down causation and other concepts familiar from the complex systems theory. Lying at the heart of vital eukaryotic processes are chromatin structure, organization and dynamics. Epigenetics provides striking examples of how bottom-up genetic and top-down epigenetic causation intermingle. The fundamental question then arises of how causal efficacy should be attributed to biological information. A proposal is made to implement explicit downward causation by coupling information directly to the dynamics of chromatin, thus permitting the coevolution of dynamical laws and states, and opening up a new sector of dynamical systems theory that promises to display rich self-organizing and self-complexifying behaviour.
doi:10.1098/rsfs.2011.0070
PMCID: PMC3262298  PMID: 22419988
epigenetics; emergence; causality
25.  Epigenetic Inheritance: A Contributor to Species Differentiation? 
DNA and Cell Biology  2012;31(Suppl 1):S-11-S-16.
Multiple epigenetic states can be associated with the same genome, and transmitted through the germline for generations, to create the phenomenon of epigenetic inheritance. This form of inheritance is mediated by complex and highly diverse components of the chromosome that associate with DNA, control its transcription, and are inherited alongside it. But, how extensive, and how stable, is the information carried in the germline by the epigenome? Several known examples of epigenetic inheritance demonstrate that it has the ability to create selectable traits, and thus to mediate Darwinian evolution. Here we discuss the possibility that epigenetic inheritance is responsible for some stable characteristics of species, focusing on a recent comparison of the human and chimpanzee methylomes which reveals that somatic methylation states are related to methylation states in the germline. Interpretation of this finding highlights the potential significance of germline epigenetic states, as well as the challenge of investigating a form of inheritance with complex and unfamiliar rules.
doi:10.1089/dna.2012.1643
PMCID: PMC3460613  PMID: 22966965

Results 1-25 (918255)