The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase
The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase
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DOI：
10.1093/nar/gkg332
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发表时间：
2003-05-01
影响因子：
14.9
通讯作者：
Kouzarides, T
中科院分区：
文献类型：
--
作者：
Fuks, F;Hurd, PJ;Kouzarides, T
DNA甲基转移酶，DNMT，是哺乳动物体内负责DNA甲基化的酶，从而导致基因沉默。DNA甲基化的抑制部分是通过甲基CpG结合蛋白MeCP2的募集而介导的。最近，MeCP2被证明在H3的Lys9处关联并促进组蛋白甲基化，这是参与基因沉默的关键的表观遗传修饰。在这里，我们表明，内源性DNMT3A主要与组蛋白H3-K9甲基转移酶活性有关，其次与H3-K4酶活性有关。与酶活性的关联是由DNMT3A保守的PHD-like基序介导的。与DNMT3A结合的H3-K9组蛋白甲基转移酶可能是H3-K9特异性的SUV39H1酶，因为我们发现它在体外和体内都与DNMT3A相互作用，使用其类似PhD的基序。我们发现SUV39H1也与Dnmt1结合，并且与这些相互作用一致，SUV39H1可以从核提取液中纯化DNA甲基转移酶活性。此外，我们还发现，SUV39H1相互作用的伙伴HP1beta直接与Dnmt1和DNMT3A结合，并且天然的HP1beta与DNA甲基转移酶活性有关。我们的数据显示，负责DNA甲基化的酶和组蛋白甲基化之间存在直接联系。这些结果通过这两个全球表观遗传修饰之间的相互作用，进一步证实了自增强抑制性染色质状态的概念。
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.