MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
Genes Dev. 2020 Jul 1;34(13-14):931-949. doi: 10.1101/gad.336487.120. Epub 2020 May 21.
Polycomb group (PcG) proteins silence gene expression by chemically and physically modifying chromatin. A subset of PcG target loci are compacted and cluster in the nucleus; a conformation that is thought to contribute to gene silencing. However, how these interactions influence gross nuclear organization and their relationship with transcription remains poorly understood. Here we examine the role of Polycomb-repressive complex 1 (PRC1) in shaping 3D genome organization in mouse embryonic stem cells (mESCs). Using a combination of imaging and Hi-C analyses, we show that PRC1-mediated long-range interactions are independent of CTCF and can bridge sites at a megabase scale. Impairment of PRC1 enzymatic activity does not directly disrupt these interactions. We demonstrate that PcG targets coalesce in vivo, and that developmentally induced expression of one of the target loci disrupts this spatial arrangement. Finally, we show that transcriptional activation and the loss of PRC1-mediated interactions are separable events. These findings provide important insights into the function of PRC1, while highlighting the complexity of this regulatory system.
多梳抑制复合物（PcG）蛋白通过化学和物理修饰染色质来沉默基因表达。PcG 的一组靶基因座被压缩并在核内聚集；这种构象被认为有助于基因沉默。然而，这些相互作用如何影响核的整体组织及其与转录的关系仍知之甚少。在这里，我们研究了多梳抑制复合物 1（PRC1）在塑造小鼠胚胎干细胞（mESC）中三维基因组组织中的作用。我们使用成像和 Hi-C 分析的组合，表明 PRC1 介导的长距离相互作用独立于 CTCF，并且可以在兆碱基尺度上连接位点。PRC1 酶活性的损伤不会直接破坏这些相互作用。我们证明 PcG 靶标在体内聚集，并且靶标基因座之一的发育诱导表达破坏了这种空间排列。最后，我们表明转录激活和 PRC1 介导的相互作用的丧失是可分离的事件。这些发现为 PRC1 的功能提供了重要的见解，同时突出了这个调控系统的复杂性。
