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:

DNA methyltransferase Dnmt1 associates with histone deacetylase activity

Nature Genetics volume 24, pages 88–91 (2000)Cite this article

Abstract

The DNA methyltransferase Dnmt1 is responsible for cytosine methylation in mammals and has a role in gene silencing1,2,3,4. DNA methylation represses genes partly by recruitment of the methyl-CpG-binding protein MeCP2, which in turn recruits a histone deacetylase activity5,6. Here we show that Dnmt1 is itself associated with histone deacetylase activity in vivo. Consistent with this association, we find that one of the known histone deacetylases, HDAC1, has the ability to bind Dnmt1 and can purify methyltransferase activity from nuclear extracts. We have identified a transcriptional repression domain in Dnmt1 that functions, at least partly, by recruiting histone deacetylase activity and shows homology to the repressor domain of the trithorax-related protein HRX (also known as MLL and ALL-1). Our data show a more direct connection between DNA methylation and histone deacetylation than was previously considered. We suggest that the process of DNA methylation, mediated by Dnmt1, may depend on or generate an altered chromatin state via histone deacetylase activity.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Dnmt1 actively represses transcription using sequences that overlap the HRX repression domain.
Figure 2: Dnmt1 686–812 represses transcription in a TSA-sensitive manner and has the ability to interact with the HDAC1 deacetylase.
Figure 3: The Dnmt1-interacting region of HDAC1 associates with methyltransferase activity.
Figure 4: DNA methyltransferase coimmunoprecipitates with HDAC1 from transfected cell extracts and associates with histone deacetylase activity in vivo.

Similar content being viewed by others

References

  1. 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 

  2. Tate, P.H. & Bird, A.P. Effects of DNA methylation on DNA-binding proteins and gene expression. Curr. Opin. Genet. Dev. 3, 226–231 (1993).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Siegfried, Z., et al. DNA methylation represses transcription in vivo. Nature Genet. 22, 203–206 (1999).

    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. 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 

  7. Ma, Q., et al. Analysis of the murine All-1 gene reveals conserved domains with human ALL-1 and identifies a motif shared with DNA methyltransferases. Proc. Natl Acad. Sci. USA 90, 6350–6354 (1993).

    Article  CAS  Google Scholar 

  8. Cross, S.H., Meehan, R.R., Nan, X. & Bird, A. A component of the transcriptional repressor MeCP1 shares a motif with DNA methyltransferase and HRX proteins. Nature Genet. 16, 256–259 (1997).

    Article  CAS  Google Scholar 

  9. Prasad, R. et al. Domains with transcriptional regulatory activity within the ALL1 and AF4 proteins involved in acute leukemia. Proc. Natl Acad. Sci. USA 92, 12160–12164 (1995).

    Article  CAS  Google Scholar 

  10. Struhl, K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 12, 599–606 (1998).

    Article  CAS  Google Scholar 

  11. Kouzarides, T. Histone acetylases and deacetylases in cell proliferation. Curr. Opin. Genet. Dev. 9, 40–48 (1999).

    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. Miska, E.A. et al. HDAC4 deacetylase associates with and represses the MEF2 transcription factor. EMBO J. 18, 5099–5107 (1999).

    Article  CAS  Google Scholar 

  14. Brehm, A. et al. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391, 597–601 (1998).

    Article  CAS  Google Scholar 

  15. 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 

  16. Magnaghi-Jaulin, L. et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391, 601–605 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Zhang, Y. et al. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13, 1924–1935 (1999).

    Article  CAS  Google Scholar 

  20. 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 

  21. 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 

  22. Jeddeloh, J.A., 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 

  23. Okano, M., Xie, S. & Li, E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nature Genet. 19, 219–220 (1998).

    Article  CAS  Google Scholar 

  24. Hagemeier, C., Cook, A. & Kouzarides, T. The retinoblastoma protein binds E2F residues required for activation in vivo and TBP binding in vitro. Nucleic Acids Res. 21, 4998–5004 (1993).

    Article  CAS  Google Scholar 

  25. Milner, J., Ponder, B., Hughes-Davies, L., Seltmann, M. & Kouzarides, T. Transcriptional activation functions in BRCA2. Nature 386, 772–773 (1997).

    Article  CAS  Google Scholar 

  26. Morkel, M., Wenkel, J., Bannister, A.J., Kouzarides, T. & Hagemeier, C. An E2F-like repressor of transcription. Nature 390, 567–568 (1997).

    Article  CAS  Google Scholar 

  27. Hagemeier, C., Walker, S., Caswell, R., Kouzarides, T. & Sinclair, J. The human cytomegalovirus 80-kilodalton but not the 72-kilodalton immediate-early protein transactivates heterologous promoters in a TATA box-dependent mechanism and interacts directly with TFIID. J. Virol. 66, 4452–4456 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Taunton, J., Hassig, C.A. & Schreiber, S.L. Amammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408–411 (1996).

    Article  CAS  Google Scholar 

  29. Ramchandani, S., MacLeod, A.R., Pinard, M., von Hofe, E. & Szyf, M. Inhibition of tumorigenesis by a cytosine-DNA, methyltransferase, antisense oligodeoxynucleotide. Proc. Natl Acad. Sci. USA 94, 684–689 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank L.S.-H. Chuang, S. Pradhan and M. Szyf for technical advice on methyltransferase assays; T.H. Bestor for the pMIG7 construct; and M. Szyf for the Metcat2 antibody. F.F. was supported by a European Community Training and Mobility of Researchers fellowship. W.A.B. was supported by a scholarship from the South African National Research Foundation. Research in the T.K. lab is supported by a programme grant from the Cancer Research Campaign (DR11).

Author information

Author notes

  1. François Fuks and Wendy A. Burgers: These authors contributed equally to this work.

Authors and Affiliations

  1. Wellcome/CRC Institute and Department of Pathology, Cambridge University, Cambridge, UK

    François Fuks, Wendy A. Burgers, Alexander Brehm, Luke Hughes-Davies & Tony Kouzarides

Authors
  1. François Fuks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wendy A. Burgers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander Brehm
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luke Hughes-Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tony Kouzarides
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tony Kouzarides.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fuks, F., Burgers, W., Brehm, A. et al. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 24, 88–91 (2000). https://doi.org/10.1038/71750

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/71750

This article is cited by

Search

Advanced 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