Department of Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, MI, USA.
Department of Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Cell Rep. 2020 Jan 14;30(2):465-480.e6. doi: 10.1016/j.celrep.2019.12.039.
How ubiquitous transcription factors (TFs) coordinate temporal inputs from broadly expressed epigenetic factors to control cell fate remains poorly understood. Here, we uncover a molecular relationship between p53, an abundant embryonic TF, and WDR5, an essential member of the MLL chromatin modifying complex, that regulates mouse embryonic stem cell fate. Wild-type Wdr5 or transient Wdr5 knockout promotes a distinct pattern of global chromatin accessibility and spurs neuroectodermal differentiation through an RbBP5-dependent process in which WDR5 binds to, and activates transcription of, neural genes. Wdr5 rescue after its prolonged inhibition targets WDR5 to mesoderm lineage-specifying genes, stimulating differentiation toward mesoderm fates in a p53-dependent fashion. Finally, we identify a direct interaction between WDR5 and p53 that enables their co-recruitment to, and regulation of, genes known to control cell proliferation and fate. Our results unmask p53-dependent mechanisms that temporally integrate epigenetic WDR5 inputs to drive neuroectoderm and mesoderm differentiation from pluripotent cells.
广泛表达的表观遗传因子如何从时间上协调转录因子（TFs），以控制细胞命运，目前仍知之甚少。在这里，我们揭示了一种分子关系，即丰富的胚胎 TF p53 与 MLL 染色质修饰复合物的必需成员 WDR5 之间的关系，该关系调节着小鼠胚胎干细胞的命运。野生型 Wdr5 或瞬时 Wdr5 敲除通过一种 RbBP5 依赖性过程促进了广泛的染色质可及性的独特模式，并刺激神经外胚层分化，其中 WDR5 结合并激活神经基因的转录。在其长期抑制后，Wdr5 的恢复将 WDR5 靶向中胚层谱系限定基因，以 p53 依赖的方式刺激向中胚层命运的分化。最后，我们鉴定了 WDR5 和 p53 之间的直接相互作用，使它们能够共同募集并调节已知控制细胞增殖和命运的基因。我们的研究结果揭示了依赖于 p53 的机制，这些机制可从时间上整合表观遗传 WDR5 的输入，以驱动多能细胞的神经外胚层和中胚层分化。
