Blackledge Neil P, Farcas Anca M, Kondo Takashi, King Hamish W, McGouran Joanna F, Hanssen Lars L P, Ito Shinsuke, Cooper Sarah, Kondo Kaori, Koseki Yoko, Ishikura Tomoyuki, Long Hannah K, Sheahan Thomas W, Brockdorff Neil, Kessler Benedikt M, Koseki Haruhiko, Klose Robert J
Laboratory of Chromatin Biology and Transcription, Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.
Laboratory of Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
Cell. 2014 Jun 5;157(6):1445-1459. doi: 10.1016/j.cell.2014.05.004. Epub 2014 May 22.
Chromatin modifying activities inherent to polycomb repressive complexes PRC1 and PRC2 play an essential role in gene regulation, cellular differentiation, and development. However, the mechanisms by which these complexes recognize their target sites and function together to form repressive chromatin domains remain poorly understood. Recruitment of PRC1 to target sites has been proposed to occur through a hierarchical process, dependent on prior nucleation of PRC2 and placement of H3K27me3. Here, using a de novo targeting assay in mouse embryonic stem cells we unexpectedly discover that PRC1-dependent H2AK119ub1 leads to recruitment of PRC2 and H3K27me3 to effectively initiate a polycomb domain. This activity is restricted to variant PRC1 complexes, and genetic ablation experiments reveal that targeting of the variant PCGF1/PRC1 complex by KDM2B to CpG islands is required for normal polycomb domain formation and mouse development. These observations provide a surprising PRC1-dependent logic for PRC2 occupancy at target sites in vivo.
多梳抑制复合物PRC1和PRC2固有的染色质修饰活性在基因调控、细胞分化和发育中起着至关重要的作用。然而，这些复合物识别其靶位点并共同发挥作用以形成抑制性染色质结构域的机制仍知之甚少。有人提出，PRC1募集到靶位点是通过一个分级过程发生的，这依赖于PRC2的预先成核和H3K27me3的定位。在这里，我们在小鼠胚胎干细胞中使用从头靶向分析意外地发现，PRC1依赖的H2AK119ub1导致PRC2和H3K27me3的募集，从而有效地启动一个多梳结构域。这种活性仅限于变体PRC1复合物，基因敲除实验表明，KDM2B将变体PCGF1/PRC1复合物靶向到CpG岛是正常多梳结构域形成和小鼠发育所必需的。这些观察结果为体内靶位点上PRC2的占据提供了一个惊人的PRC1依赖性逻辑。
