Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation

Abstract

Methylation of DNA at the dinucleotide CpG is essential for mammalian development and is correlated with stable transcriptional silencing1,2,3. This transcriptional silencing has recently been linked at a molecular level to histone deacetylation through the demonstration of a physical association between histone deacetylases and the methyl CpG-binding protein MeCP2 (refs 4,5). We previously purified a histone deacetylase complex from Xenopus laevis egg extracts that consists of six subunits, including an Rpd3-like deacetylase, the RbA p48/p46 histone-binding protein and the nucleosome-stimulated ATPase Mi-2 (ref. 6). Similar species were subsequently isolated from human cell lines7,8,9, implying functional conservation across evolution. This complex represents the most abundant form of deacetylase in amphibian eggs and cultured mammalian cells6,7,8,9. Here we identify the remaining three subunits of this enzyme complex. One of them binds specifically to methylated DNA in vitro and molecular cloning reveals a similarity to a known methyl CpG-binding protein. Our data substantiate the mechanistic link between DNA methylation, histone deacetylation and transcriptional silencing.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sequence comparisons.
Figure 2: Selective associations of Mi-2 complex components Mta1-like and MBD3 with methylated DNA.
Figure 3: MBD3, MBD2 and MeCP2 selectively bind methylated DNA.
Figure 4: Absence of demethylase activity from the Mi-2 complex.

Similar content being viewed by others

References

  1. Bird, A. et al. Studies of DNA methylation in animals. J. Cell Sci. 19 (suppl.), 37–39 ( 1995).

    Article  CAS  Google Scholar 

  2. Siegfried, Z. & Cedar, H. DNA methylation: a molecular lock. Curr. Biol. 7, R305–R307 (1997).

    Article  CAS  Google Scholar 

  3. Li, E., Bestor, T.H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

    Article  CAS  Google Scholar 

  4. 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 

  5. 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 

  6. Wade, P.A., Jones, P.L., Vermaak, D. & Wolffe, A.P. A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr. Biol. 8, 843–846 (1998).

    Article  CAS  Google Scholar 

  7. Zhang, Y., LeRoy, G., Seelig, H.-P., Lane, W.S. & Reinberg, D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95, 279–289 (1998).

    Article  CAS  Google Scholar 

  8. Tong, J.K., Hassig, C.A., Schnitzler, G.R., Kingston, R.E. & Schreiber, S.L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395, 917–921 (1998).

    Article  CAS  Google Scholar 

  9. Xue, Y. et al. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol. Cell 2, 851–861 (1998).

    Article  CAS  Google Scholar 

  10. Fernandez, J., Andrews, L. & Mische, S.M. An improved method for enzymatic digestion of polyvinylidene defluoride-bound proteins for internal sequence analysis. Anal. Biochem. 214, 112–117 ( 1994).

    Article  Google Scholar 

  11. Ausubel, F.M. et al. Current Protocols in Molecular Biology (John Wiley and Sons, New York, 1995).

    Google Scholar 

  12. 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 

  13. Futamara, M. et al. Molecular cloning, mapping, and characterization of a novel human gene MTA1-L1, showing homology to a metastasis associated gene, MTA1. J. Hum. Genet. 44, 52– 56 (1999).

    Article  Google Scholar 

  14. Toh, Y., Pencil, S.D. & Nicolson, G.L. A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. J. Biol. Chem. 269, 22958– 22963 (1994).

    CAS  PubMed  Google Scholar 

  15. Toh, Y. et al. Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis. Int. J. Cancer 74, 459–463 (1997).

    Article  CAS  Google Scholar 

  16. Solari, F., Bateman, A. & Ahringer, J. The Caenorabditis elegans genes egl-27 and egr-1 are similar to MTA1, a member of a chromatin regulatory complex, and are redundantly required for embryonic patterning. Development 126, 2483–2494 ( 1999).

    CAS  PubMed  Google Scholar 

  17. Wong, J. et al. Distinct requirements for chromatin assembly in transcriptional repression by thyroid hormone receptor and histone deacetylase. EMBO J. 17, 520–534 ( 1998).

    Article  CAS  Google Scholar 

  18. Vermaak, D., Wade, P.A., Jones, P.L., Shi, Y.-B. & Wolffe, A.P. Functional analysis of the SIN3-histone deacetylase RPD3-RbAp48-histone H4 connection in the Xenopus oocyte. Mol. Cell. Biol. 19, 5847–5860 (1999).

    Article  CAS  Google Scholar 

  19. Scanlan, M.J. et al. Characterization of human colon cancer antigens recognized by autologous antibodies. Int. J. Cancer 76, 652–658 (1998).

    Article  CAS  Google Scholar 

  20. 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 

  21. Chandler, S.P., Guschin, D., Landsberger, N. & Wolffe, A.P. The methyl-CpG binding transcriptional repressor MeCP2 stably associates with nucleosomal DNA. Biochemistry (in press). 38, 7008–7018 (1999).

    Article  CAS  Google Scholar 

  22. Simmen, M.W. et al. Nonmethylated transposable elements and methylated genes in a chordate genome. Science 283, 1164– 1167 (1999).

    Article  CAS  Google Scholar 

  23. Walsh, C.P. & Bestor, T.H. Cytosine methylation and mammalian development. Genes Dev. 13, 26– 34 (1999).

    Article  CAS  Google Scholar 

  24. Jeddeloh, J., Stokes, T.L. & Richards, E.J. Maintenance of genomic methylation requires a SWI2/SNF2-like protein. Nature Genet. 22, 94– 97 (1999).

    Article  CAS  Google Scholar 

  25. Kehle, J. et al. dMi-2, a hunchback-interacting protein that functions in Polycomb repression. Science 282, 1897 –1900 (1998).

    Article  CAS  Google Scholar 

  26. Kim, J. et al. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity 10, 345 –355 (1999).

    Article  CAS  Google Scholar 

  27. Martienssen, R. & Henikoff, S. The House and Garden guide to chromatin remodelling. Nature Genet. 22, 6–7 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Vautier, D., Besombes, D., Chassoux, D., Aubry, F. & Debey, P. Redistribution of nuclear antigens linked to cell proliferation and RNA processing in mouse oocytes and early embryos. Mol. Reprod. Dev. 38, 119– 130 (1994).

    Article  CAS  Google Scholar 

  30. Aubry, F., Mattei, M.-G. & Galibert, F. Identification of a human 17p-located cDNA encoding a protein of the Snf2-like helicase family. Eur. J. Biochem. 254, 558–564 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Y. Toh for anti-MTA1 antisera and B. Hendrich for plasmids for expression of recombinant mouse Mbd2b and Mbd3. Protein sequence determination was performed by the Protein/DNA Technology Center of the Rockefeller University. E.B. was supported by a fellowship from the Ministerio de Educacion y Cultura, Spain. P.L.J. was supported by a PRAT fellowship, NIGMS, NIH.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alan P. Wolffe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wade, P., Gegonne, A., Jones, P. et al. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet 23, 62–66 (1999). https://doi.org/10.1038/12664

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/12664

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing