Fukuda Kei, Shimura Chikako, Shinkai Yoichi
Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako, 351-0198, Japan.
Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu, 400-8510, Japan.
Epigenetics Chromatin. 2025 May 2;18(1):26. doi: 10.1186/s13072-025-00589-3.
Heterochromatin is a fundamental component of eukaryotic chromosome architecture, crucial for genome stability and cell type-specific gene regulation. In mammalian nuclei, heterochromatin forms condensed B compartments, distinct from the transcriptionally active euchromatic A compartments. Histone H3 lysine 9 and lysine 27 trimethylation (H3K9me3 and H3K27me3) are two major epigenetic modifications that enrich constitutive and facultative heterochromatin, respectively. Previously, we found that the redistribution of H3K27me3 following the loss of H3K9 methylation contributes to heterochromatin maintenance, while the simultaneous loss of both H3K27me3 and H3K9 methylation induces heterochromatin decondensation in mouse embryonic fibroblasts. However, the spatial positioning of B compartments largely persists, suggesting additional mechanisms are involved.
In this study, we investigated the role of H2AK119 monoubiquitylation (uH2A), a repressive chromatin mark deposited by Polycomb Repressive Complex 1 (PRC1), in maintaining heterochromatin structure following the loss of H3K9 and H3K27 methylation. We observed that uH2A and H3K27me3 are independently enriched in B compartments after H3K9 methylation loss. Despite the absence of H3K9me3 and H3K27me3, uH2A remained localized and contributed to heterochromatin retention. These results suggest that PRC1-mediated uH2A functions independently and cooperatively with H3K27me3 to maintain heterochromatin organization originally created by H3K9 methylation.
Our findings highlight a compensatory role for uH2A in preserving heterochromatin structure after the loss of other repressive chromatin modifications. The PRC1-uH2A pathway plays a critical role in maintaining the integrity of B compartments and suggests that heterochromatin architecture is supported by a network of redundant epigenetic mechanisms in mammalian cells.
异染色质是真核染色体结构的基本组成部分，对基因组稳定性和细胞类型特异性基因调控至关重要。在哺乳动物细胞核中，异染色质形成浓缩的B区室，与转录活跃的常染色质A区室不同。组蛋白H3赖氨酸9和赖氨酸27三甲基化（H3K9me3和H3K27me3）是两种主要的表观遗传修饰，分别富集组成型和兼性异染色质。此前，我们发现H3K9甲基化缺失后H3K27me3的重新分布有助于异染色质维持，而H3K27me3和H3K9甲基化同时缺失会诱导小鼠胚胎成纤维细胞中的异染色质解聚。然而，B区室的空间定位在很大程度上仍然存在，这表明还涉及其他机制。
在本研究中，我们研究了H2AK119单泛素化（uH2A）的作用，它是由多梳抑制复合物1（PRC1）沉积的一种抑制性染色质标记，在H3K9和H3K27甲基化缺失后维持异染色质结构。我们观察到H3K9甲基化缺失后，uH2A和H3K27me3在B区室中独立富集。尽管没有H3K9me3和H3K27me3，uH2A仍保持定位并有助于异染色质保留。这些结果表明，PRC1介导的uH2A独立发挥作用，并与H3K27me3协同维持最初由H3K9甲基化形成的异染色质组织。
我们的研究结果突出了uH2A在其他抑制性染色质修饰缺失后保留异染色质结构中的补偿作用。PRC1 - uH2A途径在维持B区室的完整性方面起着关键作用，并表明异染色质结构由哺乳动物细胞中冗余的表观遗传机制网络支持。
