Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, RNA Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
Nat Commun. 2022 Aug 6;13(1):4601. doi: 10.1038/s41467-022-32295-z.
Polycomb group (PcG) proteins are known to repress developmental genes during embryonic development and tissue homeostasis. Here, we report that PCGF6 controls neuroectoderm specification of human pluripotent stem cells (PSCs) by activating SOX2 gene. Human PSCs with PCGF6 depletion display impaired neuroectoderm differentiation coupled with increased mesendoderm outcomes. Transcriptome analysis reveals that de-repression of the WNT/β-catenin signaling pathway is responsible for the differentiation of PSC toward the mesendodermal lineage. Interestingly, PCGF6 and MYC directly interact and co-occupy a distal regulatory element of SOX2 to activate SOX2 expression, which likely accounts for the regulation in neuroectoderm differentiation. Supporting this notion, genomic deletion of the SOX2-regulatory element phenocopies the impaired neuroectoderm differentiation, while overexpressing SOX2 rescues the neuroectoderm phenotype caused by PCGF6-depletion. Together, our study reveals that PCGF6 can function as lineage switcher between mesendoderm and neuroectoderm in human PSCs by both suppression and activation mechanisms.
多梳抑制复合物（PcG）蛋白在胚胎发育和组织稳态过程中被证实可抑制发育基因的表达。在此，我们报道 PCGF6 通过激活 SOX2 基因来控制人类多能干细胞（hPSC）的神经外胚层特异性。PCGF6 耗竭的 hPSC 显示出神经外胚层分化受损，同时中胚层和内胚层结果增加。转录组分析表明，WNT/β-catenin 信号通路的去抑制是 PSC 向中胚层谱系分化的原因。有趣的是，PCGF6 和 MYC 直接相互作用并共同占据 SOX2 的远端调控元件以激活 SOX2 的表达，这可能解释了其在神经外胚层分化中的调控作用。支持这一观点，SOX2 调控元件的基因组缺失可模拟神经外胚层分化受损，而过表达 SOX2 可挽救 PCGF6 耗竭引起的神经外胚层表型。综上所述，我们的研究揭示了 PCGF6 可通过抑制和激活机制在 hPSC 中充当中胚层和神经外胚层之间的谱系转换开关。
