Department of Biochemistry, University of Oxford, Oxford, UK.
Nat Struct Mol Biol. 2021 Oct;28(10):811-824. doi: 10.1038/s41594-021-00661-y. Epub 2021 Oct 4.
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.
多梳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，多梳抑制复合物 1 和 2（PRC1 和 PRC2）结合靶基因，并利用组蛋白修饰依赖性反馈机制形成多梳染色质域，抑制转录。PRC1 和 PRC2 在这些位点的活性的相关性使得很难发现驱动基因抑制的多梳染色质域的特定成分，并从机制上理解如何实现这一点。在这里，我们通过利用基于快速降解结构域的方法和时分辨析基因组学，在动力学上剖析了多梳介导的抑制作用，并发现 PRC1 独立于 PRC2 发挥作用，以抵消 RNA 聚合酶 II 的结合和转录起始。通过单细胞基因表达分析，我们揭示了 PRC1 在细胞群体中均匀作用，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性转录调控提供了一个机制和概念框架。
