Department of Ophthalmology & Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall St., Ann Arbor, MI 48105, USA.
Department and Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Stem Cell Reports. 2021 Nov 9;16(11):2642-2658. doi: 10.1016/j.stemcr.2021.10.002. Epub 2021 Oct 28.
p53 alterations occur during culture of pluripotent stem cells (PSCs), but the significance of these events on epigenetic control of PSC fate determination remains poorly understood. Wdr5 deletion in p53-null (DKO) mouse ESCs (mESCs) leads to impaired self-renewal, defective retinal neuroectoderm differentiation, and de-repression of germ cell/meiosis (GCM)-specific genes. Re-introduction of a WDR5 mutant with defective H3K4 methylation activity into DKO ESCs restored self-renewal and suppressed GCM gene expression but failed to induce retinal neuroectoderm differentiation. Mechanistically, mutant WDR5 targets chromatin that is largely devoid of H3K4me3 and regulates gene expression in p53-null mESCs. Furthermore, MAX and WDR5 co-target lineage-specifying chromatin and regulate chromatin accessibility of GCM-related genes. Importantly, MAX and WDR5 are core subunits of a non-canonical polycomb repressor complex 1 responsible for gene silencing. This function, together with canonical, pro-transcriptional WDR5-dependent MLL complex H3K4 methyltransferase activity, highlight how WDR5 mediates crosstalk between transcription and repression during mESC fate choice.
p53 改变发生在多能干细胞（PSCs）的培养过程中，但这些事件对 PSC 命运决定的表观遗传控制的意义仍知之甚少。p53 缺失（DKO）鼠胚胎干细胞（mESCs）中的 Wdr5 缺失导致自我更新受损、视网膜神经外胚层分化缺陷和生殖细胞/减数分裂（GCM）特异性基因去抑制。将具有缺陷 H3K4 甲基化活性的 WDR5 突变体重新引入 DKO ESCs 中恢复了自我更新并抑制了 GCM 基因表达，但未能诱导视网膜神经外胚层分化。从机制上讲，突变型 WDR5 靶向缺乏 H3K4me3 的染色质，并调节 p53 缺失的 mESCs 中的基因表达。此外，MAX 和 WDR5 共同靶向谱系特异性染色质，并调节 GCM 相关基因的染色质可及性。重要的是，MAX 和 WDR5 是负责基因沉默的非典型多梳抑制复合物 1 的核心亚基。该功能与经典的、转录前依赖 WDR5 的 MLL 复合物 H3K4 甲基转移酶活性一起，突出了 WDR5 如何在 mESC 命运选择过程中介导转录和抑制之间的串扰。
