Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly.
In mammals, heterochromatin is characterized by DNA methylation at CpG dinucleotides and methylation at lysine 9 of histone H3. It is currently unclear whether there is a coordinated transmission of these two epigenetic modifications through DNA replication. Here we show that the methyl-CpG binding protein MBD1 forms a stable complex with histone H3-K9 methylase SETDB1. Moreover, during DNA replication, MBD1 recruits SETDB1 to the large subunit of chromatin assembly factor CAF-1 to form an S phase-specific CAF-1/MBD1/SETDB1 complex that facilitates methylation of H3-K9 during replication-coupled chromatin assembly. In the absence of MBD1, H3-K9 methylation is lost at multiple genomic loci and results in activation of p53BP2 gene, normally repressed by MBD1 in HeLa cells. Our data suggest a model in which H3-K9 methylation by SETDB1 is dependent on MBD1 and is heritably maintained through DNA replication to support the formation of stable heterochromatin at methylated DNA.
School of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, United Kingdom.
Shireen A
SA
Sarraf
Irina
I
Stancheva
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D018899:CpG Islands; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D046911:Macromolecular Substances; D008745:Methylation; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011496:Protein Methyltransferases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase; D014157:Transcription Factors; D020798:Two-Hybrid System Techniques
D051017:Apoptosis Regulatory Proteins; C489780:CNOT8 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006657:Histones; C066141:MBD1 protein, human; D046911:Macromolecular Substances; D011506:Proteins; D034741:RNA, Small Interfering; C090468:TP53BP2 protein, human; D014157:Transcription Factors; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human; D008239:Lysine