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.

The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation

Abstract

Histone methylation and DNA methylation cooperatively regulate chromatin structure and gene activity. How these two systems coordinate with each other remains unclear. Here we study the biological function of lysine-specific demethylase 1 (LSD1, also known as KDM1 and AOF2), which has been shown to demethylate histone H3 on lysine 4 (H3K4) and lysine 9 (H3K9)1,2. We show that LSD1 is required for gastrulation during mouse embryogenesis. Notably, targeted deletion of the gene encoding LSD1 (namely, Aof2) in embryonic stem (ES) cells induces progressive loss of DNA methylation. This loss correlates with a decrease in DNA methyltransferase 1 (Dnmt1) protein, as a result of reduced Dnmt1 stability. Dnmt1 protein is methylated in vivo, and its methylation is enhanced in the absence of LSD1. Furthermore, Dnmt1 can be methylated by Set7/9 (also known as KMT7) and demethylated by LSD1 in vitro. Our findings suggest that LSD1 demethylates and stabilizes Dnmt1, thus providing a previously unknown mechanistic link between the histone and DNA methylation systems.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Aof2 is required for early embryogenesis.
Figure 2: LSD1 deficiency in ES cells results in growth and differentiation defects.
Figure 3: LSD1 deficiency results in Dnmt1 reduction and DNA hypomethylation.
Figure 4: Dnmt1 is a substrate for LSD1.

References

  1. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Wang, J. et al. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 446, 882–887 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Tamaru, H. & Selker, E.U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Jackson, J.P., Lindroth, A.M., Cao, X. & Jacobsen, S.E. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416, 556–560 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Lehnertz, B. et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr. Biol. 13, 1192–1200 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Vire, E. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871–874 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Esteve, P.O. et al. Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev. 20, 3089–3103 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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  PubMed  Google Scholar 

  10. Lei, H. et al. De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development 122, 3195–3205 (1996).

    CAS  PubMed  Google Scholar 

  11. Okano, M., Bell, D.W., Haber, D.A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Kouskouti, A., Scheer, E., Staub, A., Tora, L. & Talianidis, I. Gene-specific modulation of TAF10 function by SET9-mediated methylation. Mol. Cell 14, 175–182 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Chuikov, S. et al. Regulation of p53 activity through lysine methylation. Nature 432, 353–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Huang, J. et al. Repression of p53 activity by Smyd2-mediated methylation. Nature 444, 629–632 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Sampath, S.C. et al. Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol. Cell 27, 596–608 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Huang, J. et al. p53 is regulated by the lysine demethylase LSD1. Nature 449, 105–108 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Schmidt, D.M. & McCafferty, D.G. trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 46, 4408–4416 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Kurash, J.K. et al. Methylation of p53 by Set7/9 mediates p53 acetylation and activity in vivo. Mol. Cell 29, 392–400 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Ding, F. & Chaillet, J.R. In vivo stabilization of the Dnmt1 (cytosine-5)-methyltransferase protein. Proc. Natl. Acad. Sci. USA 99, 14861–14866 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Agoston, A.T. et al. Increased protein stability causes DNA methyltransferase 1 dysregulation in breast cancer. J. Biol. Chem. 280, 18302–18310 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Sun, L. et al. Phosphatidylinositol 3-kinase/protein kinase B pathway stabilizes DNA methyltransferase I protein and maintains DNA methylation. Cell. Signal. 19, 2255–2263 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Chen, T. et al. Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells. Nat. Genet. 39, 391–396 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Chen, T., Ueda, Y., Dodge, J.E., Wang, Z. & Li, E. Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol. Cell. Biol. 23, 5594–5605 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen, T., Ueda, Y., Xie, S. & Li, E. A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation. J. Biol. Chem. 277, 38746–38754 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank S. Kadam and G.A. Baltus for sharing the ChIP-on-chip data and for critically reading the manuscript; Y. Shi (Harvard Medical School) for providing Aof2 cDNA; A. Ho, T. He, B. Zhang, Q. Shen and H. Fan for technical assistance; and X. Cheng, R. Valdez, X. Mao and colleagues in the Epigenetics Program at Novartis for discussions.

Author information

Authors and Affiliations

Authors

Contributions

T.C. and E.L. conceived the study; J.W. and T.C. designed the experiments and wrote the paper; J.W., F. Gaudet, E.L. and T.C. analyzed data; J.W., S.H., J.K.K., H.L., F. Gay, J.B., H.S., W.S., H.C. and T.C. carried out the experiments; and G.X. produced anti-Dnmt1.

Corresponding authors

Correspondence to En Li or Taiping Chen.

Ethics declarations

Competing interests

All authors except G.X. are employees of Novartis Institutes for Biomedical Research.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Table 1 (PDF 1701 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, J., Hevi, S., Kurash, J. et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet 41, 125–129 (2009). https://doi.org/10.1038/ng.268

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.268

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