Hashimoto , Vertino &

Epigenetics, the cell-type-specific interpretation of genetic material, relies on DNA methylation and post-translational histone modifications to regulate gene function. Nucleosomes, the fundamental building unit that packages DNA, consist of approximately 146 bp of DNA wrapped approximately 1.8-times around a histone octamer that is evolutionarily conserved [1]. Histones are subject to considerable post-translational modifications including acetylation, methylation, ubiquitylation and sumoylation of lysine residues and methylation of arginine residues [2]. The combinatorial pattern of DNA and histone modifications constitutes an epigenetic ‘code’ that shapes gene-expression patterns by enabling or restricting the transcriptional potential of genomic domains. The code is written by sequence and site-specific modification enzymes and interpreted by effector molecules that mediate the assembly of higher-order chromatin structures. Epigenetic regulation plays a fundamental role in gene expression [3], DNA replication [4] and, recombination and repair [5], and is responsible for stem cell development [6] and cellular differentiation [7]. Moreover, alterations in epigenetic modifications accompany the aging process and contribute to the pathogenesis of cancer [8–14] and degenerative diseases [15,16]. One broad theme that has emerged is that a web of interactions tightly coordinates the modification of a segment of DNA and its associated histones, particularly histone H3. This article focuses on three protein domains (ATRX–Dnmt3–Dnmt3L [ADD], Cys–X–X–Cys [CXXC] and the methylCpG-binding domain [MBD]) and how they characterize the functional links between histone and DNA modification in mammalian cells. In particular we consider the relationship between DNA CpG methylation and histone H3 methylation on lysines 4 and 9 [17–23]. DNA methylation and histone lysine methylation are intimately connected with one another [17,19–21]. In fact, genomescale DNA methylation profiles suggest that DNA methylation is correlated to histone methylation patterns [18]. Specifically, DNA methylation is associated with the absence of H3K4 methylation (H3K4me0) and the presence of H3K9 methylation, but has little correlation with methylation of H3K27 [22]. In vivo studies support a molecular link between the mechanisms that maintain The combinatorial pattern of DNA and histone modifications constitutes an epigenetic ‘code’ that shapes gene-expression patterns by enabling or restricting the transcriptional potential of genomic domains. DNA methylation is associated with histone modifications, particularly the absence of histone H3 lysine 4 methylation (H3K4me0) and the presence of H3K9 methylation. This article focuses on three protein domains (ATRX–Dnmt3–Dnmt3L [ADD], Cys–X–X–Cys [CXXC] and the methyl-CpG-binding domain [MBD]) and the functional implications of domain architecture in the mechanisms linking histone methylation and DNA methylation in mammalian cells. The DNA methyltransferase DNMT3a and its accessory protein DNMT3L contain a H3K4me0-interacting ADD domain that links the DNA methylation reaction with unmodified H3K4. The H3K4 methyltransferase MLL1 contains a CpG-interacting CXXC domain that may couple the H3K4 methylation reaction to unmethylated DNA. Another H3K4 methyltransferase, SET1, although lacking an intrinsic CXXC domain, interacts directly with an accessory protein CFP1 that contains the same domain. The H3K9 methyltransferase SETDB1 contains a putative MBD that potentially links the H3K4 methylation reaction to methylated DNA or may do so through the interaction with the MBD containing protein MBD1. Finally, we consider the domain structure of the DNA methyltransferase DNMT1, its accessory protein UHRF1 and their associated proteins, and propose a mechanism by which DNA methylation and histone methylation may be coordinately maintained through mitotic cell division, allowing for the transmission of parental DNA and for the histone methylation patterns to be copied to newly replicated chromatin.