The transcriptional repressors Polycomb repressive complex 1 (PRC1) and PRC2 are required to maintain cell fate during embryonic development. PRC1 and PRC2 catalyze distinct histone modifications, establishing repressive chromatin at shared targets. How PRC1, which consists of canonical PRC1 (cPRC1) and variant PRC1 (vPRC1) complexes, and PRC2 cooperate to silence genes and support mouse embryonic stem cell (mESC) self-renewal is unclear. Using combinatorial genetic perturbations, we show that independent pathways of cPRC1 and vPRC1 are responsible for maintenance of H2A monoubiquitylation and silencing of shared target genes. Individual loss of PRC2-dependent cPRC1 or PRC2-independent vPRC1 disrupts only one pathway and does not impair mESC self-renewal capacity. However, loss of both pathways leads to mESC differentiation and activation of a subset of lineage-specific genes co-occupied by relatively high levels of PRC1/PRC2. Thus, parallel pathways explain the differential requirements for PRC1 and PRC2 and provide robust silencing of lineage-specific genes.

转录阻遏物Polycomb Repressing Complex 1（PRC1）和PRC2是维持胚胎发育过程中细胞命运所必需的。PRC1和PRC2催化不同的组蛋白修饰，在共有靶标上建立了抑制性染色质。尚不清楚PRC1如何由规范的PRC1（cPRC1）和变体PRC1（vPRC1）复合体组成，以及PRC2如何使基因沉默并支持小鼠胚胎干细胞（mESC）自我更新。使用组合的遗传扰动，我们表明cPRC1和vPRC1的独立途径负责维持H2A单泛素化和沉默的共享目标基因。独立丢失PRC2的cPRC1或不依赖PRC2的vPRC1只会中断一条途径，并且不会损害mESC的自我更新能力。然而，两条途径的缺失都会导致mESC分化，并激活相对较高水平的PRC1 / PRC2共同占据的特定于谱系的基因的子集。因此，平行途径解释了PRC1和PRC2的差异需求，并提供了谱系特异性基因的强大沉默。