Retinoblastoma tumor suppressor protein-dependent methylation of histone H3 lysine 27 is associated with irreversible cell cycle exit.
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.
Blais
Alexandre
A
Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa K1H 8M5, Canada.
van Oevelen
Chris J C
CJ
Margueron
Raphaël
R
Acosta-Alvear
Diego
D
Dynlacht
Brian David
BD
D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D019175:DNA Methylation; D016195:G2 Phase / Q000235:genetics; D020869:Gene Expression Profiling; D020868:Gene Silencing / Q000502:physiology; D018816:Genes, cdc / Q000502:physiology; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D032448:Myoblasts, Skeletal / Q000378:metabolism*; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics
D018797:Cell Cycle Proteins; D006657:Histones; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D008239:Lysine