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.
Sarraf
Shireen A
SA
School of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, United Kingdom.
Stancheva
Irina
I
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