title: Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription.
abstract: The Dnmt3a DNA methyltransferase is essential for mammalian development and is responsible for the generation of genomic methylation patterns, which lead to transcriptional silencing. Here, we show that Dnmt3a associates with RP58, a DNA-binding transcriptional repressor protein found at transcriptionally silent heterochromatin. Dnmt3a acts as a co-repressor for RP58 in a manner that does not require its de novo methyltransferase activity. Like other characterized co-repressors, Dnmt3a associates with the histone deacetylase HDAC1 using its ATRX-homology domain. This domain of Dnmt3a represents an independent transcriptional repressor domain whose silencing functions require HDAC activity. These results identify Dnmt3a as a co-repressor protein carrying deacetylase activity and show that Dnmt3a can be targeted to specific regulatory foci via its association with DNA-binding transcription factors.
authors.affiliation: Wellcome/CRC Institute and Department of Pathology, Cambridge University, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: F
authors.initials: F
authors.lastname: Fuks
authors.forename: W A
authors.initials: WA
authors.lastname: Burgers
authors.forename: N
authors.initials: N
authors.lastname: Godin
authors.forename: M
authors.initials: M
authors.lastname: Kasai
authors.forename: T
authors.initials: T
authors.lastname: Kouzarides
mesh_terms: D001665:Binding Sites; D002461:Cell Line, Transformed; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004265:DNA Helicases; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000378:metabolism; D020868:Gene Silencing; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D000075924:X-linked Nuclear Protein
chemical_list: D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C115048:ZBTB18 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein