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

TitleRetinoblastoma tumor suppressor protein-dependent methylation of histone H3 lysine 27 is associated with irreversible cell cycle exit.
Publication TypeJournal Article
Year of Publication2007
AuthorsBlais A, van Oevelen CJC, Margueron R, Acosta-Alvear D, Dynlacht BDavid
JournalJ Cell Biol
Volume179
Issue7
Pagination1399-412
Date Published2007 Dec 31
ISSN1540-8140
KeywordsAnimals, Cell Cycle, Cell Cycle Proteins, Cell Differentiation, Cell Division, Cell Line, DNA Methylation, G2 Phase, Gene Expression Profiling, Gene Silencing, Genes, cdc, Histones, Lysine, Mice, Myoblasts, Skeletal, Retinoblastoma Protein, Retinoblastoma-Like Protein p107, Retinoblastoma-Like Protein p130, RNA Interference
Abstract

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.

DOI10.1083/jcb.200705051
Alternate JournalJ. Cell Biol.
PubMed ID18166651
PubMed Central IDPMC2373492
Grant ListCA77245 / CA / NCI NIH HHS / United States
GM067132 / GM / NIGMS NIH HHS / United States