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Functional cooperation between HP1 and DNMT1 mediates gene silencing

¹ Department of Biological Chemistry, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA; ² New England Biolabs, Ipswich, Massachusetts 01938, USA

Mammalian euchromatic gene silencing results from the combined repressive effects of histone and DNA methyltransferases. Little is known of the mechanism by which these enzymes cooperate to induce silencing. Here we show that mammalian HP1 family members mediate communication between histone and DNA methyltransferases. In vitro, methylation of histone 3 Lys 9 by G9a creates a binding platform for HP1, , and . DNMT1 interacts with HP1 resulting in increased DNA methylation on DNA and chromatin templates in vitro. The functional and physical interaction can be recapitulated in vivo. Binding of GAL4-HP1 to a reporter construct is sufficient to induce repression and DNA methylation in DNMT1 wild-type but not DNMT1-null cells. Additionally, silencing of the Survivin gene coincides with recruitment of G9a and HP1 in DNMT1 wild-type but not null cells. We conclude that direct interactions between HP1 and DNMT1 mediate silencing of euchromatic genes.

[Keywords: HP1; DNMT1; G9a; histone methylation; DNA methyltransferase]

Received January 31, 2007; revised version accepted March 26, 2007.

E-MAIL mcarey{at}mednet.ucla.edu; FAX (310) 206-9598.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1536807

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