The Polycomb repressive system plays a fundamental role in controlling gene expression during mammalian development. To achieve this, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) bind target genes and use histone modification-dependent feedback mechanisms to form Polycomb chromatin domains and repress transcription. The inter-relatedness of PRC1 and PRC2 activity at these sites has made it difficult to discover the specific components of Polycomb chromatin domains that drive gene repression and to understand mechanistically how this is achieved. Here, by exploiting rapid degron-based approaches and time-resolved genomics, we kinetically dissect Polycomb-mediated repression and discover that PRC1 functions independently of PRC2 to counteract RNA polymerase II binding and transcription initiation. Using single-cell gene expression analysis, we reveal that PRC1 acts uniformly within the cell population and that repression is achieved by controlling transcriptional burst frequency. These important new discoveries provide a mechanistic and conceptual framework for Polycomb-dependent transcriptional control.

Polycomb 抑制系统在哺乳动物发育过程中控制基因表达方面发挥着重要作用。为了实现这一目标，Polycomb 抑制复合物 1 和 2（PRC1 和 PRC2）结合靶基因，并使用组蛋白修饰依赖性反馈机制形成 Polycomb 染色质结构域并抑制转录。这些位点上 PRC1 和 PRC2 活性的相互关联性使得很难发现驱动基因抑制的 Polycomb 染色质结构域的特定成分，也很难从机制上理解这是如何实现的。在这里，通过利用基于降解决定子的快速方法和时间分辨基因组学，我们动态剖析了 Polycomb 介导的抑制，并发现 PRC1 独立于 PRC2 发挥作用，以抵消 RNA 聚合酶 II 结合和转录起始。通过单细胞基因表达分析，我们揭示了 PRC1 在细胞群中的作用一致，并且通过控制转录爆发频率来实现抑制。这些重要的新发现为多梳依赖的转录控制提供了机制和概念框架。