title: The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase.
abstract: 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 modification 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 specific SUV39H1 enzyme since we find that it interacts both in vitro and in vivo with Dnmt3a, using its PHD-like motif. We find 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 HP1beta, a SUV39H1-interacting partner, binds directly to Dnmt1 and Dnmt3a and that native HP1beta 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 modifications.
authors.affiliation: Wellcome Trust/CR UK Institute and Department of Pathology, Cambridge University, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: François
authors.initials: F
authors.lastname: Fuks
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hurd
authors.forename: Rachel
authors.initials: R
authors.lastname: Deplus
authors.forename: Tony
authors.initials: T
authors.lastname: Kouzarides
mesh_terms: D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D000090205:DNA Methyltransferase 3A; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D058619:Maltose-Binding Proteins; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000715593:CBX1 protein, human; D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; C000717967:DNMT3A protein, human; D006657:Histones; D058619:Maltose-Binding Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619380:DNMT1 protein, human; D005982:Glutathione Transferase; D008239:Lysine