Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex
Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex
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作者：
Nan, XS;Ng, HH;Bird, A
在动物基因组中，5 'CpG（胞嘧啶-鸟嘌呤）序列中的胞嘧啶残基通常在合成后甲基化。CpG甲基化参与哺乳动物发育过程中某些基因的长期沉默（1，2）和病毒基因组的抑制（3，4）。甲基-CpG结合蛋白MeCP 1（参考文献5）和MeCP 2（参考文献6）与甲基化DNA特异性相互作用，并介导转录抑制（7-9）。在这里，我们研究了MeCP 2的抑制机制，MeCP 2是一种丰富的核蛋白，对小鼠胚胎发生至关重要（10）。MeCP 2以甲基化依赖性方式与染色体紧密结合（11，12）。它含有一个转录抑制结构域（TRD），可以在体外和体内远距离发挥GRAPHICS功能（9）。我们发现MeCP 2的一个区域与TRD相关，该区域与含有转录抑制因子mSin 3A和组蛋白脱乙酰酶的辅抑制因子复合物相关（13-19）。体内转录抑制可通过去乙酰化酶抑制剂阿司他丁A缓解（20），表明组蛋白（和/或其他蛋白质）的去乙酰化是这种抑制机制的重要组成部分。这些数据表明，两个全球性的基因调控机制，DNA甲基化和组蛋白去乙酰化，可以通过MeCP 2连接。
Cytosine residues in the sequence 5'CpG (cytosine-guanine) are often postsynthetically methylated in animal genomes. CpG methylation is involved in long-term silencing of certain genes during mammalian development(1,2) and in repression of viral genomes(3,4). The methyl-CpG-binding proteins MeCP1 (ref. 5) and MeCP2 (ref. 6) interact specifically with methylated DNA and mediate transcriptional repression(7-9). Here we study the mechanism of repression by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis(10). MeCP2 binds tightly to chromosomes in a methylation-dependent manner(11,12). It contains a transcriptional-repression domain (TRD) that canGRAPHICSfunction at a distance in vitro and in vivo(9). We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases(13-19). Transcriptional repression in vivo is relieved by the deacetylase inhibitor trichostatin A(20), indicating that deacetylation of histones (and/or of other proteins) is an essential component of this repression mechanism. The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2.