State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, 12 Xuefu Road, Nanjing, Jiangsu 210061, China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Stem Cell Reports. 2022 May 10;17(5):1198-1214. doi: 10.1016/j.stemcr.2022.02.020. Epub 2022 Mar 31.
Polycomb group proteins assemble into multi-protein complexes, known as Polycomb repressive complexes 1 and 2 (PRC1 and PRC2), that guide cell fate decisions during embryonic development. PRC1 forms an array of biochemically distinct canonical PRC1 (cPRC1) or non-canonical PRC1 (ncPRC1) complexes characterized by the mutually exclusive presence of PCGF (PCGF1-PCGF6) paralog subunit; however, whether each one of these subcomplexes fulfills a distinct role remains largely controversial. Here, by performing a CRISPR-based loss-of-function screen in embryonic stem cells (ESCs), we uncovered a previously unappreciated functional redundancy among PRC1 subcomplexes. Disruption of ncPRC1, but not cPRC1, displayed severe defects in ESC pluripotency. Remarkably, coablation of non-canonical and canonical PRC1 in ESCs resulted in exacerbation of the phenotype observed in the non-canonical PRC1-null ESCs, highlighting the importance of functional redundancy among PRC1 subcomplexes. Together, our studies demonstrate that PRC1 subcomplexes act redundantly to silence lineage-specific genes and ensure robust maintenance of ESC identity.
多梳蛋白组蛋白组装成多蛋白复合物，称为多梳抑制复合物 1 和 2（PRC1 和 PRC2），这些复合物在胚胎发育过程中指导细胞命运决定。PRC1 形成一系列生化不同的典型 PRC1（cPRC1）或非典型 PRC1（ncPRC1）复合物，其特征是 PCGF（PCGF1-PCGF6）旁系同源亚基的相互排斥存在；然而，这些亚复合物中的每一个是否都具有独特的作用仍然存在很大争议。在这里，我们通过在胚胎干细胞（ESCs）中进行基于 CRISPR 的功能丧失筛选，揭示了 PRC1 亚复合物之间以前未被重视的功能冗余。ncPRC1 的破坏，但不是 cPRC1，显示出 ESC 多能性的严重缺陷。值得注意的是，非典型 PRC1 和典型 PRC1 在 ESCs 中的共缺失导致非典型 PRC1 缺失的 ESCs 中观察到的表型恶化，突出了 PRC1 亚复合物之间功能冗余的重要性。总之，我们的研究表明，PRC1 亚复合物冗余地发挥作用，沉默谱系特异性基因，并确保 ESC 身份的稳健维持。
