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 p ostsynthetically methylated in animal genomes. CpG methylation is invo lved in long-term silencing of certain genes during mammalian developm ent(1,2) and in repression of viral genomes(3,4). The methyl-CpG-bindi ng proteins MeCP1 (ref. 5) and MeCP2 (ref. 6) interact specifically wi th methylated DNA and mediate transcriptional repression(7-9). Here we study the mechanism of repression by MeCP2, an abundant nuclear prote in 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 GRAPHICS function at a distance in vitro and in vivo(9). We show that a region of MeCP2 th at localizes with the TRD associates with a corepressor complex contai ning 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 histon es (and/or of other proteins) is an essential component of this repres sion mechanism. The data suggest that two global mechanisms of gene re gulation, DNA methylation and histone deacetylation, can be linked by MeCP2.