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

Abstract

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 development1,2 and in repression of viral genomes3,4. The methyl-CpG-binding proteins MeCP1 (ref. 5) and MeCP2 (ref. 6) interact specifically with methylated DNA and mediate transcriptional repression7,8,9. Here we study the mechanism of repression by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis10. MeCP2 binds tightly to chromosomes in a methylation-dependent manner11,12. It contains a transcriptional-repression domain (TRD) that can function at a distance in vitro and in vivo9. We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases13,14,15,16,17,18,19. Transcriptional repression in vivo is relieved by the deacetylase inhibitor trichostatin A20, 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.

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Figure 1: Interaction of MeCP2 with mSin3A and histone deacetylases.
Figure 2: Co-immunoprecipitation of mSin3, MeCP2 and histone deacetylase activity from rat brain nuclear extracts.
Figure 3: MeCP2 interacts with mSin3A, but not with HDACs.
Figure 4: Relief of TRD-mediated repression of transcription by the deacetylase inhibitor TSA.

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Acknowledgements

We thank J. Davidson and A. Greig for technical assistance, E. Seto for anti-HDAC2 antiserum and T. Kouzarides for the HDAC1 expression plasmid. The work was supported by a grant from the N.I.H. (to R.N.E.) and by grants from The Wellcome Trust (to A.B. and B.M.T.). H.-H.N. is a Darwin Trust scholar; C.D.L. is a Leukemia Society of America Special Fellow; and R.N.E. is an American Cancer Society Research Professor.

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Correspondence to Adrian Bird.

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Nan, X., Ng, HH., Johnson, C. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998). https://doi.org/10.1038/30764

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