E2f1–3 switch from activators in progenitor cells to repressors in differentiating cells

Abstract

The in vivo function of E2f transcription factors has been a matter of debate. Here it is shown that E2f1–3 contribute to the activation of cell cycle genes in dividing progenitor cells during mouse development but are dispensable for cell division. However, in differentiating cells, E2f1–3 act as repressors to facilitate cell cycle exit. The in vivo function of E2f transcription factors has been a matter of debate. The effects of E2f1, E2f2 and E2f3 triple deficiency are now examined in murine embryonic stem cells, embryos and small intestines. E2f1–3 are shown to function as transcriptional activators in normal dividing progenitor cells; however, contrary to the current view, they are dispensable for cell division but are necessary for cell survival. In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase1,2. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines. We show that in normal dividing progenitor cells E2f1–3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1–3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1–3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f1–3 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f1–3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.