Functional cooperation between HP1 and DNMT1 mediates gene silencing.
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 HP1alpha, beta, and gamma. 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.
Smallwood
Andrea
A
Department of Biological Chemistry, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
Estève
Pierre-Olivier
PO
Pradhan
Sriharsa
S
Carey
Michael
M
D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing / Q000502:physiology*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011496:Protein Methyltransferases; D000077022:Survivin
C107489:BIRC5 protein, human; C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D000090266:Chromobox Protein Homolog 5; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D011495:Histone-Lysine N-Methyltransferase