The Rb/chromatin connection and epigenetic control: opinion

The balance between cell differentiation and proliferation is regulated at the transcriptional level, In the cell cycle, the transition from G1 to S p hase (G1/S transition) is of paramount importance in this regard, Indeed, i t is only before this point that cells can be oriented toward the different iation pathway: beyond, cells progress into the cycle in an autonomous mann er. The G1/S transition is orchestrated by the transcription factor E2F, E2 F controls the expression of a group of checkpoint genes whose products are required either for the G1-to-S transition itself or for DNA replication ( e.g. DNA polymerase alpha), E2F activity is repressed in growth-arrested ce lls and in early G1, and is activated at mid-to-late G1, E2F is controlled by the retinoblastoma tumor suppressor protein Rb, Rb represses E2F mainly by recruiting chromatin remodeling factors (histone deacetylases and SWI/SN F complexes), the DNA methyltransferase DNMT1, and a histone methyltransfer ase, This review will focus on the molecular mechanisms of E2F repression b y Rb during the cell cycle and during cell-cycle exit by differentiating ce lls. A model in which Rb irreversibly represses E2F-regulated genes in diff erentiated cells by an epigenetic mechanism linked to heterochromatin, and involving histone H3 and promoter DNA methylation, is discussed.