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Review
. 2010 Oct;2(5):657-69.
doi: 10.2217/epi.10.44.

Molecular coupling of DNA methylation and histone methylation

Hideharu Hashimoto  1 , Paula M Vertino, Xiaodong Cheng
Affiliations
Review

Molecular coupling of DNA methylation and histone methylation

Hideharu Hashimoto et al. Epigenomics. 2010 Oct.

Abstract

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 Dnmt 3L 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.

Keywords: ADD; CXXC; CpG-binding domain; H3K4me0-binding domain; MBD; SRA; hemi-methyl-CpG-binding domain; methyl-CpG-binding domain.

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Figures

Figure 1
Figure 1. H3K4me0-interacting proteins
(A) Domain architecture of known H3K4me0-interacting proteins containing either ADD domain or PHD finger. ATRX interacts with histone H3.3. (B) Sequence alignment of ADD domains and PHD fingers known to interact with H3K4me0. (C) Model of the reactions that regulate DNA methylation by Dnmt3a/3L. Recognition of H3K4me0 by the ADD domain of DNMT3 directs the DNA methylation reaction. The ‘m’ in a circle indicates one or more methyl groups in DNA (5-methyl-cytosine) or histone lysines (methylated lysine). (D) Structure of the ADD domain of Dnmt3a (PDB ID: 3A1B) showing the interaction with the histone H3 tail. ADD: ATRX–Dnmt3–Dnmt3L; Chromo: Chromosome; PDB: Protein database; PHD: Plant homeodomain; RING: Really interesting new gene; SRA: SET and RING associated.
Figure 2
Figure 2. CpG-interacting proteins
(A) Domain architecture of CXXC domain-containing proteins. Inset: model of the H3K4 methylation reaction by MLL/SET1. CXXC domain-mediated binding to unmethylated CpGs directs the methylation of H3K4 by MLL/SET1 proteins. CXXC4 was initially named as IDAX, and decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling. CXXC5 (also known as RINF), which was initially identified in a large-scale functional proteomics mapping of human genes, activates the NF-kB and MAPK signaling pathways, and its expression correlates with retinoid-induced differentiation of leukemic cells and with cytokine-induced myelopoiesis of normal CD34+ progenitors, is required for DNA damage-induced p53 activation and is a BMP4-regulated modulator of Wnt signaling in neural stem cells. (B) Ribbon diagram (top left) and stick diagram (top right) of the MLL1 CXXC domain in complex with unmethylated DNA. Note the recognition of CpG by a Lys–Gln dipeptide in the major groove. Sequence alignment of CXXC domains including candidates from Drosophila and Caenorhabditis elegans (Bottom). BAH: Bromo-adjacent homology domain; CHD: Chromodomain-helicase-DNA-binding protein; CXXC: Cys–X–X–Cys; DSBH: Double-stranded β-helix; FYRC: FY-rich domain C-terminal region; FYRN: FY-rich domain N-terminal region; IDAX: Inhibiton of the Dvl and Axin complex in the Wnt signaling pathway; MBD: Methyl-CpG-binding domain; PCNA: Proliferating cell nuclear antigen; PHD: Plant homeodomain; RINF: Retinoid-inducible nuclear factor; SET: Su(var)3-9, Enhancer-of-zeste, Trithorax; TTRF: Target to replication foci.
Figure 3
Figure 3. Methyl-CpG-binding domain-containing proteins
(A) Model of the reactions that regulate H3K9 methylation by SUV39H1 or SETDB1. Recognition of methylated CpGs by the MBD of MBD1 directs methylation of H3K9me3. Inset: MBD structures of MeCP2 and MBD1 in complex with methyl-CpG DNA, respectively. (B) Sequence alignment of known and putative MBD domains. BAZ2-A and -B are two related proteins containing a MBD, DDT, PHD-type zinc finger and bromodomain. DDT is predicted to be a DNA binding domain (∼60 residues in length). BAZ2A, also known as TTF-I interacting peptide 5 or TIP5; hWALp3, is a component of the chromatin remodeling complex NoRC, a complex that mediates silencing of a fraction of rDNA. DDT: DNA-binding homeobox and different transcription factors; HDAC: Histone deacetylase; MBD: Methyl-CpG-binding domain; PDB: Protein database; PHD: Plant homeodomain; SET: Su(var)3-9, Enhancer-of-zeste, Trithorax.
Figure 4
Figure 4. Putative model of the coupling of UHRF1 and Dnmt1 to maintain the fidelity of DNA methylation during DNA replication
The binding of the SRA domain of UHRF1 to hemi-methylated CpG sites generated by new strand synthesis recruits Dnmt1, allowing for displacement and subsequent methylation of the daughter strand. SRA: SET and RING associated.
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