Abstract
E2F transcription factors are central regulators of cell division and cell fate decisions. E2F4 often represents the predominant E2F activity in cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. This role for E2F4 is independent of the RB family. Furthermore, E2F4 functionally interacts with chromatin regulators associated with gene activation and we observed decreased histone acetylation at the promoters of cell cycle genes and E2F targets upon loss of E2F4 in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that provide insights into the biology of rapidly dividing cells.
Highlights
E2F transcription factors are central regulators of cell division and cell fate decisions
E2F4 is highly expressed in mouse ES cells. Mouse embryonic stem cells (mESCs) are rapidly dividing cells in which the RB family proteins are constitutively hyperphosphorylated due to constitutive Cyclin-dependent kinase (Cdk) activity[25]
Previous chromatin immunoprecipitation (ChIP) studies revealed that ectopically-expressed E2F4 can regulate numerous loci in the genome of mESCs, including genes coding for histones[28], often in conjunction with the cell cycle activator c-MYC29, suggesting that E2F4 can be nuclear and access chromatin in mESCs
Summary
E2F transcription factors are central regulators of cell division and cell fate decisions. We show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. The “classical” E2Fs (E2F1, E2F2, E2F3a, E2F3b, E2F4, and E2F5) can physically associate with the RB family proteins, which regulate their activity (reviewed in[4,5,6]) These E2Fs can be further subdivided into canonical “repressors” (E2F3b, E2F4, E2F5) and “activators” (E2F1, E2F2, E2F3a) depending on their purported activity at the promoters of cell cycle genes. During S phase, hyperphosphorylation of the RB family proteins prevents their binding to E2F4, and E2F4 is exported to the cytoplasm[10], allowing activator E2Fs, which possess a nuclear localization signal, to promote the transcription of cell cycle genes. The co-incidence of E2F4 release from RB family members and its export from the nucleus supports a model in which E2F4 does not act as a transcriptional activator[11,12]
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