Article
- The EMBO Journal (2008) 27, 2691 - 2701
- doi:10.1038/emboj.2008.193
Published online: 25 September 2008
Subject Category:
DNA methylation in ES cells requires the lysine methyltransferase G9a but not its catalytic activity
Kevin B Dong1, Irina A Maksakova1,2, Fabio Mohn3, Danny Leung1, Ruth Appanah1, Sandra Lee1, Hao W Yang1, Lucia L Lam1, Dixie L Mager1,2, Dirk Schübeler3, Makoto Tachibana4,5, Yoichi Shinkai4,5 and Matthew C Lorincz1
- Department of Medical Genetics, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Kyoto, Japan
- Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan
Correspondence to:
Matthew C Lorincz, Department of Medical Genetics, Life Sciences Institute Room 5-507, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Tel.: +604 827 3965; Fax: +604 822 5348; E-mail: mlorincz@interchange.ubc.ca
Received 2 April 2008; Accepted 21 August 2008
Abstract
Histone H3K9 methylation is required for DNA methylation and silencing of repetitive elements in plants and filamentous fungi. In mammalian cells however, deletion of the H3K9 histone methyltransferases (HMTases) Suv39h1 and Suv39h2 does not affect DNA methylation of the endogenous retrovirus murine leukaemia virus, indicating that H3K9 methylation is dispensable for DNA methylation of retrotransposons, or that a different HMTase is involved. We demonstrate that embryonic stem (ES) cells lacking the H3K9 HMTase G9a show a significant reduction in DNA methylation of retrotransposons, major satellite repeats and densely methylated CpG-rich promoters. Surprisingly, demethylated retrotransposons remain transcriptionally silent in G9a-/- cells, and show only a modest decrease in H3K9me2 and no decrease in H3K9me3 or HP1
binding, indicating that H3K9 methylation per se is not the relevant trigger for DNA methylation. Indeed, introduction of catalytically inactive G9a transgenes partially 'rescues' the DNA methylation defect observed in G9a-/- cells. Taken together, these observations reveal that H3K9me3 and HP1 recruitment to retrotransposons occurs independent of DNA methylation in ES cells and that G9a promotes DNA methylation independent of its HMTase activity.
Keywords:
- chromatin,
- DNA methylation,
- ERV,
- H3K9 methylation,
- HP1
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