National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Department of Bioinformatics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
Mol Cell. 2024 Apr 4;84(7):1191-1205.e7. doi: 10.1016/j.molcel.2024.02.017. Epub 2024 Mar 7.
Polycomb repressive complex 1 (PRC1) is a key transcriptional regulator in development via modulating chromatin structure and catalyzing histone H2A ubiquitination at Lys119 (H2AK119ub1). H2AK119ub1 is one of the most abundant histone modifications in mammalian cells. However, the function of H2AK119ub1 in polycomb-mediated gene silencing remains debated. In this study, we reveal that H2AK119ub1 has two distinct roles in gene expression, through differentially modulating chromatin compaction mediated by canonical PRC1 and the linker histone H1. Interestingly, we find that H2AK119ub1 plays a positive role in transcription through interfering with the binding of canonical PRC1 to nucleosomes and therefore counteracting chromatin condensation. Conversely, we demonstrate that H2AK119ub1 facilitates H1-dependent chromatin condensation and enhances the silencing of developmental genes in mouse embryonic stem cells, suggesting that H1 may be one of several possible pathways for H2AK119ub1 in repressing transcription. These results provide insights and molecular mechanisms by which H2AK119ub1 differentially fine-tunes developmental gene expression.
多梳抑制复合物 1（PRC1）是一种关键的转录调节剂，通过调节染色质结构和催化组蛋白 H2A 在赖氨酸 119 上的泛素化（H2AK119ub1）来发挥作用。H2AK119ub1 是哺乳动物细胞中最丰富的组蛋白修饰之一。然而，H2AK119ub1 在多梳介导的基因沉默中的功能仍存在争议。在这项研究中，我们揭示了 H2AK119ub1 通过差异调节由典型 PRC1 和连接组蛋白 H1 介导的染色质紧缩，在基因表达中具有两个不同的作用。有趣的是，我们发现 H2AK119ub1 通过干扰典型 PRC1 与核小体的结合，从而抵消染色质浓缩，在转录中发挥正向作用。相反，我们证明 H2AK119ub1 促进 H1 依赖性染色质凝聚，并增强小鼠胚胎干细胞中发育基因的沉默，表明 H1 可能是 H2AK119ub1 抑制转录的几种可能途径之一。这些结果提供了见解和分子机制，说明 H2AK119ub1 如何差异精细调节发育基因表达。
