Nan X, Ng H H, Johnson C A, Laherty C D, Turner B M, Eisenman R N, Bird A
Institute of Cell and Molecular Biology, University of Edinburgh, UK.
Nature. 1998 May 28;393(6683):386-9. doi: 10.1038/30764.
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 and in repression of viral genomes. The methyl-CpG-binding proteins MeCP1 and MeCP2 interact specifically with methylated DNA and mediate transcriptional repression. Here we study the mechanism of repression by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis. MeCP2 binds tightly to chromosomes in a methylation-dependent manner. It contains a transcriptional-repression domain (TRD) that can function at a distance in vitro and in vivo. 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. Transcriptional repression in vivo is relieved by the deacetylase inhibitor trichostatin A, 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.
在动物基因组中，5'CpG（胞嘧啶-鸟嘌呤）序列中的胞嘧啶残基常常在合成后被甲基化。CpG甲基化参与哺乳动物发育过程中某些基因的长期沉默以及病毒基因组的抑制。甲基-CpG结合蛋白MeCP1和MeCP2与甲基化DNA特异性相互作用并介导转录抑制。在此，我们研究MeCP2的抑制机制，MeCP2是一种丰富的核蛋白，对小鼠胚胎发育至关重要。MeCP2以甲基化依赖的方式紧密结合染色体。它包含一个转录抑制结构域（TRD），该结构域在体外和体内均可远距离发挥作用。我们发现，MeCP2中与TRD定位在一起的一个区域与一个共抑制复合物相关联，该复合物包含转录抑制因子mSin3A和组蛋白脱乙酰酶。体内转录抑制可被脱乙酰酶抑制剂曲古抑菌素A解除，这表明组蛋白（和/或其他蛋白质）的去乙酰化是这种抑制机制的一个重要组成部分。这些数据表明，基因调控的两种全局机制，即DNA甲基化和组蛋白去乙酰化，可以通过MeCP2联系起来。
