Epigenetic regulation by histone methylation and histone variants (original) (raw)
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Linking DNA methylation and histone modification -patterns and paradigms
Although it is now accepted that chromatin structure has a large impact on the regulation of gene expression, little is known about how individual epigenetic marks are set up and then maintained through DNA replica-tion and cell division. Chemical modification of DNA or of chromatin-associated proteins, particularly histones, has a major influence on chromatin structure and gene expression. In animal cells, DNA can be modified by methylation of cytosine residues in CpG dinucleotides, and the N-terminal tails of histone proteins are subject to a wide range of different modifications, including acetylation, methylation, phosphorylation and ubiq-uitylation. All of these chemical changes seem to have a substantial influence on chromatin structure and gene function, which differs depending on the type and location of the modification. In this Review we take advantage of evidence from recent genetic, biochemical and microarray studies to explore the relationship between DNA methylation and histone modification, particularly focusing on methylation of histone H3 at lysine 9 (H3K9) and 27 (H3K27), which are important modifications for gene repression. Although DNA methylation and histone modification are carried out by different chemical reactions and require different sets of enzymes, there seems to be a biological relationship between the two systems that plays a part in modulating gene repression programming in the organism. We describe how DNA meth-ylation and specific histone modifications influence each other during mammalian development. It seems that the relationship can work in both directions: his-tone methylation can help to direct DNA methylation patterns, and DNA methylation might serve as a template for some histone modifications after DNA repli-cation. Recent evidence indicates that, at the molecular level, these connections might be accomplished through direct interactions between histone and DNA methyl-transferases. We then discuss how histone modification and DNA methylation can have different roles in gene silencing, with histone modifications providing labile transcriptional repression and DNA methylation being a highly stable silencing mark that is not easily reversed. Finally, we address how understanding the relationship between these two types of modification can help us to decipher the epigenetic blocks that inhibit cellular reprogramming and to understand mechanisms of gene repression in cancer. Generating modification patterns Generation of the basal bimodal DNA methylation pattern. The basic methylation pattern of the animal genome is bimodal: almost all CpG dinucleotides are methylated, except those located in CpG islands, which are to a large extent constitutively unmodified. The DNA methylation pattern is erased in the early embryo and then re-established in each individual at approximately the time of implantation 1,2. Differential methylation is established through two counteracting mechanisms: a wave of indiscriminate de novo methylation 3 and a mechanism for ensuring that CpG islands remain unmethylated. The precise details of how CpG islands are protected are not completely elucidated, but early studies using transgenic mice and transfection experiments in embryonic stem cells suggested that protection
In this review, we discuss recent advances made on his-tone methylation and its diverse functions in regulating gene expression. Methylation of histone polypeptides might be static and might mark a gene to be or not be transcribed. However, the decision to methylate or not methylate a specific residue in the histone polypeptides is an active process that requires coordination among different covalent modifications occurring at the amino termini of the histone polypeptides, the histone tails. Below, we summarize recent advances on histone meth-yltransferases, and we discuss histone methylation within the context of other histone tail modifications. Histone modifications and the histone code hypothesis
Neurotoxicity research, 2015
In multicellular organisms, all the cells are genetically identical but turn genes on or off at the right time to promote differentiation into specific cell types. The regulation of higher-order chromatin structure is essential for genome-wide reprogramming and for tissue-specific patterns of gene expression. The complexity of the genome is regulated by epigenetic mechanisms, which act at the level of DNA, histones, and nucleosomes. Epigenetic machinery is involved in many biological processes, including genomic imprinting, X-chromosome inactivation, heterochromatin formation, and transcriptional regulation, as well as DNA damage repair. In this review, we summarize the recent understanding of DNA methylation, cytosine derivatives, active and passive demethylation pathways as well as histone variants. DNA methylation is one of the well-characterized epigenetic signaling tools. Cytosine methylation of promoter regions usually represses transcription but methylation in the gene body m...
Selective targeting of histone methylation
Cell Cycle, 2011
H istones are post-translationally modified by multiple histonemodifying enzymes, which in turn influences gene expression. Much of the work in the field to date has focused on genetic, biochemical and structural characterization of these enzymes. The most recent genome-wide methods provide insights into specific recruitment of histonemodifying enzymes in vivo and, therefore, onto mechanisms of establishing a differential expression pattern. Here we focus on the recruitment mechanisms of the enzymes involved in the placement of two contrasting histone marks, histone H3 lysine 4 (H3K4) methylation and histone H3 lysine 27 (H3K27) methylation. We describe distribution of their binding sites and show that recruitment of different histone-modifying proteins can be coordinated, opposed or alternating. Specifically, genomic sites of the H3K4 histone demethylase KDM5A become accessible to its homolog KDM5B in cells with a lowered KDM5A level. The currently available data on recruitment of H3K4/H3K27 modifying enzymes suggests that the formed protein complexes are targeted in a sequential and temporal manner, but that additional, still unknown, interactions contribute to targeting specificity.
The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase
Nucleic acids research, 2003
The DNA methyltransferases, Dnmts, are the enzymes responsible for methylating DNA in mammals, which leads to gene silencing. Repression by DNA methylation is mediated partly by recruitment of the methyl-CpG-binding protein MeCP2. Recently, MeCP2 was shown to associate and facilitate histone methylation at Lys9 of H3, which is a key epigenetic modi®cation involved in gene silencing. Here, we show that endogenous Dnmt3a associates primarily with histone H3-K9 methyltransferase activity as well as, to a lesser extent, with H3-K4 enzymatic activity. The association with enzymatic activity is mediated by the conserved PHD-like motif of Dnmt3a. The H3-K9 histone methyltransferase that binds Dnmt3a is likely the H3-K9 speci®c SUV39H1 enzyme since we ®nd that it interacts both in vitro and in vivo with Dnmt3a, using its PHD-like motif. We ®nd that SUV39H1 also binds to Dnmt1 and, consistent with these interactions, SUV39H1 can purify DNA methyltransferase activity from nuclear extracts. In addition, we show that HP1b, a SUV39H1-interacting partner, binds directly to Dnmt1 and Dnmt3a and that native HP1b associates with DNA methyltransferase activity. Our data show a direct connection between the enzymes responsible for DNA methylation and histone methylation. These results further substantiate the notion of a self-reinforcing repressive chromatin state through the interplay between these two global epigenetic modi®cations.
Genes
DNA methylation is an essential part of the epigenome chromatin modification network, which also comprises several covalent histone protein post-translational modifications. All these modifications are highly interconnected, because the writers and erasers of one mark, DNA methyltransferases (DNMTs) and ten eleven translocation enzymes (TETs) in the case of DNA methylation, are directly or indirectly targeted and regulated by other marks. Here, we have collected information about the genomic distribution and variability of DNA methylation in human and mouse DNA in different genomic elements. After summarizing the impact of DNA methylation on genome evolution including CpG depletion, we describe the connection of DNA methylation with several important histone post-translational modifications, including methylation of H3K4, H3K9, H3K27, and H3K36, but also with nucleosome remodeling. Moreover, we present the mechanistic features of mammalian DNA methyltransferases and their associated...
Euchromatic histone methyltransferases (EHMTs) methylate histone and non-histone proteins. Here we uncover a novel role for EHMTs in regulating heterochromatin anchorage to the nuclear periphery (NP) via non-histone methylations. In search for mechanism, we identified EHMTs methylate LaminB1 (LMNB1) that associates with the H3K9me2 marked peripheral heterochromatin. Loss of LMNB1 methylation or EHMTs abrogates the heterochromatin anchorage from the nuclear periphery. We further demonstrate that the loss of EHMTs induced many hallmarks of aging including global reduction of H3K27 methyl marks along with altered nuclear-morphology. Keeping consistent with this, we observed gradual depletion of EHMTs, which correlated with loss of methylated LMNB1 and peripheral heterochromatin in aging human fibroblasts. Restoration of EHMT expression reverts peripheral heterochromatin defect in aged cells. Collectively our studies elucidated a new mechanism by which EHMTs regulate heterochromatin dom...
The N-terminus of histone H3 is required for de novo DNA methylation in chromatin
Proceedings of the National Academy of Sciences, 2009
DNA methylation and histone modification are two major epigenetic pathways that interplay to regulate transcriptional activity and other genome functions. Dnmt3L is a regulatory factor for the de novo DNA methyltransferases Dnmt3a and Dnmt3b. Although recent biochemical studies have revealed that Dnmt3L binds to the tail of histone H3 with unmethylated lysine 4 in vitro, the requirement of chromatin components for DNA methylation has not been examined, and functional evidence for the connection of histone tails to DNA methylation is still lacking. Here, we used the budding yeast Saccharomyces cerevisiae as a model system to investigate the chromatin determinants of DNA methylation through ectopic expression of murine Dnmt3a and Dnmt3L. We found that the N terminus of histone H3 tail is required for de novo methylation, while the central part encompassing lysines 9 and 27, as well as the H4 tail are dispensable. DNA methylation occurs predominantly in heterochromatin regions lacking ...
Regulation of chromatin structure by site-specific histone H3 methyltransferases
Nature, 2000
The organization of chromatin into higher-order structures in¯uences chromosome function and epigenetic gene regulation. Higher-order chromatin has been proposed to be nucleated by the covalent modi®cation of histone tails and the subsequent establishment of chromosomal subdomains by non-histone modi®er factors. Here we show that human SUV39H1 and murine Suv39h1Ðmammalian homologues of Drosophila Su(var)3-9 and of Schizosaccharomyces pombe clr4Ðencode histone H3-speci®c methyltransferases that selectively methylate lysine 9 of the amino terminus of histone H3 in vitro. We mapped the catalytic motif to the evolutionarily conserved SET domain, which requires adjacent cysteine-rich regions to confer histone methyltransferase activity. Methylation of lysine 9 interferes with phosphorylation of serine 10, but is also in¯uenced by preexisting modi®cations in the amino terminus of H3. In vivo, deregulated SUV39H1 or disrupted Suv39h activity modulate H3 serine 10 phosphorylation in native chromatin and induce aberrant mitotic divisions. Our data reveal a functional interdependence of site-speci®c H3 tail modi®cations and suggest a dynamic mechanism for the regulation of higher-order chromatin.