Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex

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 , 8 , 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 can function 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 , 14 , 15 , 16 , 17 , 18 , 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.