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

Nature Genetics volume 41, pages 125–129 (2009)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Epigenetics Program, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Jing Wang, Sarah Hevi, Julia K Kurash, Frédérique Gay, Jeffrey Bajko, Hui Su, Weitao Sun, François Gaudet, En Li & Taiping Chen

  2. Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Hong Lei & Hua Chang

  3. The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China

    Guoliang Xu

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  1. Jing Wang
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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.

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Correspondence to En Li or Taiping Chen.

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

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

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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

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