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MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex

Abstract

Mammalian DNA is methylated at many CpG dinucleotides. The biological consequences of methylation are mediated by a family of methyl-CpG binding proteins1,2,3,4. The best characterized family member is MeCP2, a transcriptional repressor that recruits histone deacetylases5,6,7. Our report concerns MBD2, which can bind methylated DNA in vivo and in vitro 4 and has been reported to actively demethylate DNA (ref. 8). As DNA methylation causes gene silencing, the MBD2 demethylase is a candidate transcriptional activator. Using specific antibodies, however, we find here that MBD2 in HeLa cells is associated with histone deacetylase (HDAC) in the MeCP1 repressor complex1,9. An affinity-purified HDAC1 corepressor complex10,11 also contains MBD2, suggesting that MeCP1 corresponds to a fraction of this complex. Exogenous MBD2 represses transcription in a transient assay, and repression can be relieved by the deacetylase inhibitor trichostatin A (TSA; ref. 12). In our hands, MBD2 does not demethylate DNA. Our data suggest that HeLa cells, which lack the known methylation-dependent repressor MeCP2, use an alternative pathway involving MBD2 to silence methylated genes.

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Figure 1: MBD2a binds methylated DNA specifically and is part of the methyl-CpG binding complex, MeCP1.
Figure 2: MBD2 is associated with histone deacetylases in the MeCP1 complex.
Figure 3: MBD2 can account for deacetylase-dependent repression of methylated genes in HeLa cells.
Figure 4: Absence of demethylation by in vitro-translated MBD2b.

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References

  1. Meehan, R.R., Lewis, J.D., McKay, S., Kleiner, E.L. & Bird, A.P. Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58, 499–507 (1989).

    Article  CAS  Google Scholar 

  2. Lewis, J.D. et al. Purification, sequence and cellular localisation of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905–914 (1992).

    Article  CAS  Google Scholar 

  3. Cross, S.H., Meehan, R.R., Nan, X. & Bird, A. A component of the transcriptional repressor MeCP1 is related to mammalian DNA methyltransferase and thrithorax-like protein. Nature Genet. 16, 256–259 (1997).

    Article  CAS  Google Scholar 

  4. Hendrich, B. & Bird, A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol. Cell. Biol. 18, 6538–6547 ( 1998).

    Article  CAS  Google Scholar 

  5. Nan, X., Campoy, J. & Bird, A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88, 471 –481 (1997).

    Article  CAS  Google Scholar 

  6. Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).

    Article  CAS  Google Scholar 

  7. Jones, P.L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genet. 19, 187– 191 (1998).

    Article  CAS  Google Scholar 

  8. Bhattacharya, S.K., Ramchandani, S., Cervoni, N. & Szyf, M. A mammalian protein with specific demethylase activity for mCpG DNA. Nature 397, 579–583 ( 1999).

    Article  CAS  Google Scholar 

  9. Boyes, J. & Bird, A. DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell 64 , 1123–1134 (1991).

    Article  CAS  Google Scholar 

  10. Zhang, Y., Iratni, R., Erdjument-Bromage, H., Tempst, P. & Reinberg, D. Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex. Cell 89, 357–364 ( 1997).

    Article  CAS  Google Scholar 

  11. Zhang, Y. et al. SAP30, a novel protein conserved between human and yeast, is a component of a histone deacetylase complex. Mol. Cell 1, 1021–1031 (1998).

    Article  CAS  Google Scholar 

  12. Yoshida, M., Horinouchi, S. & Beppu, T. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays 17, 423–430 ( 1995).

    Article  CAS  Google Scholar 

  13. Boyes, J. & Bird, A. Repression of genes by DNA methylation depends on CpG density and promoter strength: evidence for involvement of a methyl-CpG binding protein. EMBO J. 11, 327–333 (1992).

    Article  CAS  Google Scholar 

  14. Cameron, E.E., Bachman, K.E., Myohanen, S., Herman, J.G. & Baylin, S.B. Synergy of demethylation and histone deacetylase inhilbition in the re-expression of genes silenced in cancer. Nature Genet. 21, 103– 107 (1999).

    Article  CAS  Google Scholar 

  15. Eden, S., Hashimshony, T., Keshet, I. & Cedar, H. DNA methylation models histone acetylation. Nature 394, 842 (1998).

    Article  CAS  Google Scholar 

  16. Ng, H.-H. & Bird, A. DNA methylation and chromatin modification. Curr. Opin. Genet. Dev. 9, 158– 163 (1999).

    Article  CAS  Google Scholar 

  17. Selker, E.U. Trichostatin A causes selective loss of DNA methylation in Neurospora. Proc. Natl Acad. Sci. USA 95, 9430– 9435 (1998).

    Article  CAS  Google Scholar 

  18. Brehm, A. et al. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391, 597– 600 (1998).

    Article  CAS  Google Scholar 

  19. Magnaghi-Jaulin, L. et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391, 601– 604 (1998).

    Article  CAS  Google Scholar 

  20. Luo, R.X., Postigo, A.A. & Dean, D.C. Rb interacts with histone deacetylase to repress transcription. Cell 92, 463–473 (1998).

    Article  CAS  Google Scholar 

  21. Nan, X., Tate, P., Li, E. & Bird, A.P. DNA Methylation specifies chromosomal localization of MeCP2. Mol. Cell. Biol. 16, 414–421 (1996).

    Article  CAS  Google Scholar 

  22. Nan, X., Meehan, R.R. & Bird, A. Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res. 21, 4886–4892 (1993).

    Article  CAS  Google Scholar 

  23. Yeung, K.C., Inostroza, J.A., Mermelstein, F.H., Kannabiran, C. & Reinberg, D. Structure-function analysis of the TBP-binding protein Dr1 reveals a mechanism for repression of class II gene transcription. Genes Dev. 8, 2097– 2109 (1994).

    Article  CAS  Google Scholar 

  24. White, D.A., Belyaev, N.D. & Turner, B.M. Preparation of site-specific antibodies to acetylated histones. Methods (in press).

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Acknowledgements

We thank J. Millbrandt, M. Szyf, S. MacNeill and X. Nan for plasmids and J. Davidson and A. Greig for technical assistance. This work was supported by grants from the Wellcome Trust to A.B. and B.M.T. H.-H.N. holds a Darwin Trust Scholarship. D.R. is supported by the Howard Hughes Medical Institute and the National Institutes of Health. Y.Z. holds an NIH Post-doctoral Fellowship.

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Correspondence to Adrian Bird.

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Ng, HH., Zhang, Y., Hendrich, B. et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet 23, 58–61 (1999). https://doi.org/10.1038/12659

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