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Systems Biology in Toxicology and Environmental Health Copyright © 2015 Elsevier Inc CHAPTER 3 Systems Biology and the Epigenome Michele M. Taylor, Susan K. Murphy Contents Introduction 43 DNA Methylation 44 Molecular Basis of DNA Methylation 44 Posttranslational Histone Modifcations 46 Chromatin 50 References 52 INTRODUCTION Epigenetics is a continually evolving, emergent branch of biology initially defined by Conrad Waddington in 1942 as the mechanism by which genes bring about pheno- type [1]. This definition was expanded in 1987 by Robin Holliday to include patterns of DNA methylation that result in corresponding gene activity [2]. Cur rently, epi- genetics can be defined as the study of heritable changes in gene expression that are not attributable to alterations of the genome sequence. Epigenetics has been accepted as a biological function for many years. During development, the zygote starts in a totipotent state from which the dividing cells progressively differentiate into a myriad of cell types of subsequently narrower potential. This allows for vastly different pheno- types of cells in an individual, all of which carry an identical genome (an eye cell is different than a neural or skin cell). The genome is the complete set of genes or genetic material present in a cell. The genome includes both genes and noncoding sequences of the DNA. The epigenome includes both the histone-associated chroma- tin assembly (histones, DNA binding proteins, and the DNA) along with the patterns of genomic DNA methylation, thereby conferring the three-dimensional structure and compaction of the genomic material inside the cell nucleus. DNA methylation and histone modifications are the most extensively studied epigenetic modifications. In this chapter, we present an overview of currently understood epigenetic mecha- nisms as they relate to the regulation of single genes and larger chromosomal domains within the entirety of the epigenome. Systems Biology in Toxicology and Environmental Health Copyright © 2015 Elsevier Inc. http://dx.doi.org/10.1016/B978-0-12-801564-3.00003-1 All rights reserved. 43 44 Systems Biology in Toxicology and Environmental Health DNA METHYLATION First recognized in 1948 and now commonly referred to as the “fifth base” of DNA [3], 5-methylcytosine (5-mC) generated considerable interest and debate as researchers sought to realize its biological significance (for a review, see Ref. [4]). It is now well estab- lished that DNA methylation imparts both short- and long-term effects on gene expres- sion [5,6]. Specifically, DNA methylation can elicit long-term epigenetic silencing of particular sequences in somatic cells such as transposons, imprinted genes, and pluripo- tency-associated genes [5]. DNA methylation is an integral part of numerous cellular processes, including embryonic development, genomic imprinting, preservation of chro- mosome stability, and X chromosome inactivation [7–10]. Researchers have gained insight about DNA methylation, including the mechanisms by which it occurs and pref- erential target sequences. In-depth characterization of DNA methylation (and histone modifications) has also come from the results of the Human Roadmap Epigenomics project that has utilized high-throughput sequencing technologies to define epigenomic information across different tissue types and at different life stages in humans [11]. Given its fundamental role in transcriptional regulation, it follows that perturbation of these epigenetic marks or the enzymatic machinery that adds or removes these marks may lead to complications including developmental disorders or cancer [12]. Indeed, two independent research laboratories linked DNA methylation status and cancer in seminal papers published in 1983 [13,14]. Feinburg and Vogelstein first reported reduced DNA methylation of specific genes in human colon cancer cells compared with normal tissue [14]. Months later, Gama-Sosa et al. showed global reductions in 5-mC content of DNA obtained from various human malignancies, particularly metastases [13]. These preliminary studies paved the way for increased awareness of the importance of DNA methylation in cancer and portended the role it plays in other disorders and diseases. MOLECULAR BASIS OF DNA METHYLATION DNA methylation is the process by which the covalent addition of a methyl group (-CH3) to the 5′ carbon of a cytosine moiety generates 5-mC. DNA methylation pre- dominantly occurs in the context of cytosines that precede guanines, also known as 5′- CpG-3′ dinucleotides, or CpG sites [15]. It has also been shown to occur in CpA, CpC and CpT sequences in mammalian cells [16–18], and in fact, approximately 25% of all DNA methylation in embryonic stem cells is in nonCpG context [10]. CpGs are highly underrepresented in the genome, yet 70% of these are methylated. The remaining are unmethylated and often found in “CpG islands.” CpG islands are regions of the genome that are at least 200 base pairs in length with greater than 50% G and C contents and a ratio of observed to expected CpG frequency of at least 0.6 [16]. CpG islands are enriched in the 5′ promoter and/or exon regions of genes. Nearly 60% of human pro- moters are characterized by a high CpG content [19]. However, CpG density by itself Systems Biology and the Epigenome 45 does not influence gene expression. Instead, regulation of transcription often depends on DNA methylation status. In general, promoter-associated CpG islands are unmethylated at transcriptionally active genes; in contrast, methylation is typically associated with gene silencing [12,15,16]. The first demonstration that gene silencing occurs in diploid somatic cells by methylation (separate from X chromosome inactivation) was at the reti- noblastoma tumor suppressor gene [12]. Since then, many other tumor suppressor genes have also been found to be subjected to silencing by epigenetic mechanisms [16]. The methylation reaction that adds the 5′ cytosine moiety is catalyzed by a class of enzymes called DNA methyltransferases (DNMTs). These enzymes transfer a methyl group to the 5′ position of the cytosine ring, taking it from the universal methyl group donor S-adenosylmethionine (SAM) (Figure 1). There are five members of the DNMT family, including DNMT1, DNMT2, DNMT3a, DNMT3b, and DNMT3L [20]. DNMT1, DNMT3a, and DNMT3b inter- act with cytosine nucleotides to generate the global methylation pattern, or methylome. Figure 1 Schematic of epigenetic modifcations. DNA strands are wrapped around histone octamers, forming nucleosomes that organize into chromatin. Chromatin forms the building blocks of a chromo- some. Reversible histone modifcations occur at multiple amino acid residues via methylation, acetyla- tion, phosphorylation, ubiquitination, and sumoylation. DNA methyltransferases (DNMTs) transfer a methyl group from the methyl group donor, S-adenosylmethionine (SAM), to the 5′ position of the cytosine ring. 46 Systems Biology in Toxicology and Environmental Health These enzymes are further classified as either de novo (DNMT3a and DNMT3b) or maintenance (DNMT1) enzymes. DNMT2 and DNMT3L do not function as cytosine methyltransferases [16]. Possessing homology to DNMT3a and DNMT3b, DNMT3L stimulates de novo DNA methylation activity via DNMT3a by increasing the binding affinity to SAM [21] and also mediates transcriptional gene repression by recruiting his- tone deacetylase 1 (discussed below) [22–24]. DNMT2 does not possess the N-terminal regulatory domain that the other DNMTs share. It is thought to be involved in DNA damage response and repair [25]. DNMT1 is responsible for bestowing the methylation pattern of the parental template DNA strand to the newly synthesized DNA daughter strand as DNA replication occurs, prior to cell division. This ensures that both resulting cells have the same methylome [16]. This activity is essential for proper cell function and for the maintenance of methylation status across somatic cell division. De novo DNA methylation during embryogenesis and germ cell development is carried out by DNMT3a and DNMT3b [26]. It was discovered that 5-mC can be oxidized by ten-eleven translocation (TET) pro- teins to form 5-hydroxymethylcytosine (5-hmC), prompting a paradigm shift in our current understanding of the mechanism by which DNA methylation is reversed. 5-hmC, which is structurally similar to 5-mC, was initially discovered in cerebellar neurons as well as in embryonic stem cells [27–29]. Other mechanisms that replace 5-mC with unmethylated cytosine have also been identified and involve the activity of the TET enzymes to form 5-hmC, the deamination of 5-mC or 5-hmC through the activation induced deaminase proteins, and finally base excision repair by the DNA glycosylase family of enzymes [30]. 5-mC can also be converted by the TET proteins to 5-carboxyl- cytosine and 5-formylcytosine in the process of DNA demethylation [31]. The distinct roles of DNMT family members have been the focus of continued research and the discovery of potential multifunctionality and/or epigenetic crosstalk among them has been reported [32]. In fact, it has been demonstrated that DNMT3A and DNMT3B can function in vitro as both DNA methyltransferases and dehydroxymethylases [33]. POSTTRANSLATIONAL HISTONE MODIFICATIONS Posttranslational histone modifications are another type of epigenetic modification (Figure 2). The amino terminal tails of the four core histones, H2A, H2B, H3, and H4, are labile and receptive to a number of modifications, including acetylation, methylation, phos- phorylation, ubiquitination, and sumoylation [34,35]. Histones are tightly packaged in globular cores with
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