Synergy between Variant PRC1 Complexes Defines Polycomb-Mediated Gene Repression
Synergy between Variant PRC1 Complexes Defines Polycomb-Mediated Gene Repression
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DOI：
10.1016/j.molcel.2019.03.024
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发表时间：
2019-06-06
期刊：
影响因子：
16
通讯作者：
Klose, Robert J.
中科院分区：
文献类型：
--
作者：
Fursova, Nadezda A.;Blackledge, Neil P.;Klose, Robert J.
Polycomb系统修饰染色质并在抑制基因表达以控制正常哺乳动物发育中起重要作用。然而，定义Polycomb蛋白复合物如何实现这一点的组件和机制仍然是个谜。在这里，我们使用组合遗传扰动加上定量基因组学，以发现小鼠胚胎干细胞中Polycomb介导的基因抑制的中心决定因素。我们证明，典型的Polycomb抑制复合物1（PRC1），介导的高阶染色质结构，有助于基因阻遏。相反，我们发现了PRC1复合物变体之间出乎意料的高度协同作用，这是基因抑制的基础。我们进一步证明，变体PRC1复合物负责不同的H2A单泛素化池，这些池与Polycomb靶基因的抑制和X染色体失活期间的沉默相关。总之，这些发现揭示了Polycomb介导的基因抑制的新变体PRC1依赖性逻辑。
The Polycomb system modifies chromatin and plays an essential role in repressing gene expression to control normal mammalian development. However, the components and mechanisms that define how Polycomb protein complexes achieve this remain enigmatic. Here, we use combinatorial genetic perturbation coupled with quantitative genomics to discover the central determinants of Polycomb-mediated gene repression in mouse embryonic stem cells. We demonstrate that canonical Polycomb repressive complex 1 (PRC1), which mediates higher-order chromatin structures, contributes little to gene repression. Instead, we uncover an unexpectedly high degree of synergy between variant PRC1 complexes, which is fundamental to gene repression. We further demonstrate that variant PRC1 complexes are responsible for distinct pools of H2A monoubiquitylation that are associated with repression of Polycomb target genes and silencing during X chromosome inactivation. Together, these discoveries reveal a new variant PRC1-dependent logic for Polycomb-mediated gene repression.