Sarraf Shireen A, Stancheva Irina
School of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, United Kingdom.
Mol Cell. 2004 Aug 27;15(4):595-605. doi: 10.1016/j.molcel.2004.06.043.
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.
在哺乳动物中，异染色质的特征是CpG二核苷酸处的DNA甲基化以及组蛋白H3赖氨酸9位的甲基化。目前尚不清楚这两种表观遗传修饰是否通过DNA复制进行协同传递。在此我们表明，甲基-CpG结合蛋白MBD1与组蛋白H3-K9甲基转移酶SETDB1形成稳定复合物。此外，在DNA复制过程中，MBD1将SETDB1招募至染色质组装因子CAF-1的大亚基，形成S期特异性的CAF-1/MBD1/SETDB1复合物，该复合物在复制偶联的染色质组装过程中促进H3-K9的甲基化。在缺乏MBD1的情况下，多个基因组位点的H3-K9甲基化缺失，并导致p53BP2基因激活，该基因在HeLa细胞中通常受MBD1抑制。我们的数据提出了一个模型，其中SETDB1介导的H3-K9甲基化依赖于MBD1，并通过DNA复制得以遗传维持，以支持在甲基化DNA处形成稳定的异染色质。
