Abstract
The balance between cell differentiation and proliferation is regulated at the transcriptional level. In the cell cycle, the transition from G1 to S phase (G1/S transition) is of paramount importance in this regard. Indeed, it is only before this point that cells can be oriented toward the differentiation pathway: beyond, cells progress into the cycle in an autonomous manner. The G1/S transition is orchestrated by the transcription factor E2F. E2F 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 α). E2F activity is repressed in growth-arrested cells 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/SNF complexes), the DNA methyltransferase DNMT1, and a histone methyltransferase. This review will focus on the molecular mechanisms of E2F repression by Rb during the cell cycle and during cell-cycle exit by differentiating cells. A model in which Rb irreversibly represses E2F-regulated genes in differentiated cells by an epigenetic mechanism linked to heterochromatin, and involving histone H3 and promoter DNA methylation, is discussed.
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Acknowledgements
The authors are very grateful to Dr Didier Trouche for sharing results before publication and to Dr Francine Puvion-Dutilleul for providing an electron micrograph of the nucleus. Work in the authors' laboratory was supported by grants from the Ligue Nationale contre le Cancer, the Comité de l'Essone, and the Comité du Val de Marne, from the Association pour la Recherche sur le Cancer, and from the European 5th PCRDT (grant QLRT 1999-00866). R Ferriera was supported by a fellowship from the Comité du Val d'Oise de la Ligue Contre le Cancer, and I Naguibneva by a grant from the Association pour la Recherche sur le Cancer.
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Ferreira, R., Naguibneva, I., Pritchard, L. et al. The Rb/chromatin connection and epigenetic control: opinion. Oncogene 20, 3128–3133 (2001). https://doi.org/10.1038/sj.onc.1204337
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DOI: https://doi.org/10.1038/sj.onc.1204337
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