Department of Pediatrics, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA.
Department of Genetics, 300 Pasteur Drive, Stanford University, Stanford, CA, 94305, USA.
Nat Commun. 2019 Jul 3;10(1):2939. doi: 10.1038/s41467-019-10901-x.
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.
E2F 转录因子是细胞分裂和细胞命运决定的核心调节剂。E2F4 通常代表细胞中占主导地位的 E2F 活性。E2F4 是一种参与细胞周期停滞的转录抑制因子，其抑制活性取决于其与 RB 家族成员的相互作用。在这里，我们表明 E2F4 对于小鼠胚胎干细胞的增殖和存活是重要的。在这些细胞中，E2F4 部分作为转录激活因子起作用，促进细胞周期基因的表达。E2F4 的这种作用独立于 RB 家族。此外，E2F4 与与基因激活相关的染色质调节剂具有功能相互作用，并且我们观察到在 RB 家族突变细胞中丧失 E2F4 时，细胞周期基因和 E2F 靶标启动子处的组蛋白乙酰化降低。总之，我们的发现揭示了 E2F4 的非典型作用，为快速分裂细胞的生物学提供了新的见解。
