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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Li, E., Bestor, T.H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).
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).
Ng, H.-H. & Bird, A. DNA methylation and chromatin modification. Curr. Opin. Genet. Dev. 9, 158–163 (1999).
Siegfried, Z., et al. DNA methylation represses transcription in vivo. Nature Genet. 22, 203–206 (1999).
Nan, X., et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).
Jones, P.L., et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genet. 19, 187–191 (1998).
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).
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).
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).
Struhl, K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 12, 599–606 (1998).
Kouzarides, T. Histone acetylases and deacetylases in cell proliferation. Curr. Opin. Genet. Dev. 9, 40–48 (1999).
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).
Miska, E.A. et al. HDAC4 deacetylase associates with and represses the MEF2 transcription factor. EMBO J. 18, 5099–5107 (1999).
Brehm, A. et al. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391, 597–601 (1998).
Luo, R.X., Postigo, A.A. & Dean, D.C. Rb interacts with histone deacetylase to repress transcription. Cell 92, 463–473 (1998).
Magnaghi-Jaulin, L. et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391, 601–605 (1998).
Eden, S., Hashimshony, T., Keshet, I., Cedar, H. & Thorne, A.W. DNA methylation models histone acetylation. Nature 394, 842 (1998).
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).
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).
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).
Selker, E. U. Trichostatin A causes selective loss of DNA methylation in Neurospora. Proc. Natl Acad. Sci. USA 95, 9430–9435 (1998).
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).
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).
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).
Milner, J., Ponder, B., Hughes-Davies, L., Seltmann, M. & Kouzarides, T. Transcriptional activation functions in BRCA2. Nature 386, 772–773 (1997).
Morkel, M., Wenkel, J., Bannister, A.J., Kouzarides, T. & Hagemeier, C. An E2F-like repressor of transcription. Nature 390, 567–568 (1997).
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).
Taunton, J., Hassig, C.A. & Schreiber, S.L. Amammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408–411 (1996).
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).
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
Authors and Affiliations
Corresponding author
Rights 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
Issue Date:
DOI: https://doi.org/10.1038/71750
This article is cited by
-
DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors
Scientific Reports (2023)
-
Methylation of hypoxia-inducible factor 3 subunit alpha contributes to poor prognosis in lung adenocarcinoma
Journal of Applied Genetics (2023)
-
Early ependymal tumor with MN1-BEND2 fusion: a mostly cerebral tumor of female children with a good prognosis that is distinct from classical astroblastoma
Journal of Neuro-Oncology (2023)
-
Combined genomic and proteomic approaches reveal DNA binding sites and interaction partners of TBX2 in the developing lung
Respiratory Research (2021)
-
Unraveling the functional role of DNA demethylation at specific promoters by targeted steric blockage of DNA methyltransferase with CRISPR/dCas9
Nature Communications (2021)