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RESEARCH COMMUNICATION

pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16^INK4a tumor suppressor gene

¹ Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; ² Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; ³ Department of Pediatrics and Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA

Genetic studies have demonstrated that Bmi1 promotes cell proliferation and stem cell self-renewal with a correlative decrease of p16^INK4a expression. Here, we demonstrate that Polycomb genes EZH2 and BMI1 repress p16 expression in human and mouse primary cells, but not in cells deficient for pRB protein function. The p16 locus is H3K27-methylated and bound by BMI1, RING2, and SUZ12. Inactivation of pRB family proteins abolishes H3K27 methylation and disrupts BMI1, RING2, and SUZ12 binding to the p16 locus. These results suggest a model in which pRB proteins recruit PRC2 to trimethylate p16, priming the BMI1-containing PRC1L ubiquitin ligase complex to silence p16.

[Keywords: p16; pRB; BMI1; PRC1; PRC2; transcriptional regulation]

Received October 3, 2006; revised version accepted November 14, 2006.

E-MAIL yxiong{at}email.unc.edu; FAX (919) 966-8799.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1499407

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