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Published online
doi:10.1083/jcb.200705051
The Journal of Cell Biology, Vol. 179, No. 7, 1399-1412
The Rockefeller University Press, 0021-9525 $30.00
© Blais et al.
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Article

Retinoblastoma tumor suppressor protein–dependent methylation of histone H3 lysine 27 is associated with irreversible cell cycle exit



Alexandre Blais1, Chris J.C. van Oevelen2, Raphaël Margueron3, Diego Acosta-Alvear2, and Brian David Dynlacht2

1 Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa K1H 8M5, Canada
2 Department of Pathology, New York University Cancer Institute and 3 Department of Biochemistry, New York University School of Medicine, New York, NY 10016

Correspondence to B. Dynlacht: brian.dynlacht{at}med.nyu.edu

The retinoblastoma tumor suppressor protein (pRb) is involved in mitotic exit, promoting the arrest of myoblasts, and myogenic differentiation. However, it is unclear how permanent cell cycle exit is maintained in differentiated muscle. Using RNA interference, expression profiling, and chromatin immunoprecipitations, we show that pRb is essential for cell cycle exit and the differentiation of myoblasts and is also uniquely required to maintain this arrest in myotubes. Remarkably, we also uncover a function for the pRb-related proteins p107 and p130 as enforcers of a G2/M phase checkpoint that prevents progression into mitosis in cells that have lost pRb. We further demonstrate that pRb effects permanent cell cycle exit in part by maintaining trimethylation of histone H3 lysine 27 (H3K27) on cell cycle genes. H3K27 trimethylation silences other genes, including Cyclin D1, in a pRb-independent but polycomb-dependent manner. Thus, our data distinguish two distinct chromatin-based regulatory mechanisms that lead to terminal differentiation.

A. Blais and C.J.C. van Oevelen contributed equally to this paper.

Abbreviations used in this paper: Ccnd1, cyclin D1; ChIP, chromatin immunoprecipitation; HMTase, histone methyltransferase; MEF, mouse embryonic fibroblast; MHC, myosin heavy chain; PcG, polycomb group; pRb, retinoblastoma tumor suppressor protein; PRC, PcG repressor complex.


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