近日，华东师范大学教授翁杰敏及其小组研究出保守的H3K14ub驱动H3K9me3染色质区隔化。相关论文发表在2025年10月15日出版的《自然》杂志上。

在这里，研究小组确定G2E3是H3K14ub特异性的，周中心异染色质定位的E3连接酶。G2E3催化的H3K14ub增强了SUV39H对组蛋白H3赖氨酸9三甲基化（H3K9me3）的作用，并且是SUV39H区隔化和H3K9me3在中心周围异染色质中所特别需要的。在机制上，课题组人员发现G2E3在G2/M期高表达，并以RNA依赖的方式与有丝分裂染色体结合，催化H3K14ub，这对于随后SUV39H和HP1的序列募集至关重要。

SUV39H染色体结构域是H3K9me3和H3K14ub双重修饰的读卡器，SUV39H主要通过其H3K14ub结合活性与中心周围异染色质结合。值得注意的是，G2E3的缺失严重损害了中心周围异染色质的组织，并导致SUV39H和H3K9me3在许多常染色质区域的异常积累和广泛的转录抑制。他们的发现揭示了依赖于H3K14ub的SUV39H区隔化是中心周围异染色质形成的统一机制，这对于适当的常染色质区隔化和转录调控至关重要。

据了解，真核生物基因组划分为常染色质和异染色质具有重要的生物学意义。先前的研究表明，SUV39H读取和写入组蛋白H3赖氨酸9甲基化的自模板途径是细胞分裂过程中异染色质重组的核心机制。在裂变酵母中，哺乳动物SUV39H同源物Clr4形成含有泛素连接酶Cul4的复合体，催化H3K14单泛素化（H3K14ub）促进异染色质形成。然而，哺乳动物细胞分裂中的异染色质重组是否涉及类似的途径尚不清楚。

附：英文原文

Title: A conserved H3K14ub-driven H3K9me3 for chromatin compartmentalization

Author: Huang, Yuanyong, Sun, Yimei, Qi, Hongyun, Jiang, Quanlong, Li, Jialun, Chang, Mingzhi, Li, Xinyan, Shu, Lei, Duan, Xiaoya, Wang, Yiqin, Fang, Kailun, Mao, Hailei, Han, Mengmeng, Weng, Yuan, Zhang, Qiao, Chen, Zhaosu, Wei, Wei, Song, Gaojie, Zhang, Qiansen, Li, Jiwen, Han, Jing-Dong J., Chen, Charlie Degui, Wong, Jiemin

Issue&Volume: 2025-10-15

Abstract: Compartmentalization of eukaryotic genome into euchromatin and heterochromatin is of critical biological significance1,2,3. Previous studies have suggested a self-templating pathway involving the reading and writing of histone H3 lysine 9 methylation by SUV39H as the core mechanism for heterochromatin reassembly during cell division1,3. In fission yeast, the mammalian SUV39H homologue Clr4 forms a complex containing ubiquitin ligase Cul4, which catalyses H3K14 mono-ubiquitination (H3K14ub) to promote heterochromatin formation. However, whether heterochromatin reassembly in dividing mammalian cells involves a similar pathway is unknown. Here we identified G2E3 as an H3K14ub-specific, pericentromeric heterochromatin-localized E3 ligase. G2E3-catalysed H3K14ub potentiates histone H3 lysine 9 trimethylation (H3K9me3) by SUV39H and is specifically required for SUV39H compartmentalization and H3K9me3 in pericentromeric heterochromatin. Mechanistically, we found that G2E3 is highly expressed in G2/M phase and associates with mitotic chromosomes in an RNA-dependent manner to catalyse H3K14ub, which is essential for the subsequent sequential recruitment of SUV39H and HP1. The SUV39H chromodomain is a reader of dual H3K9me3 and H3K14ub modifications and SUV39H associates with pericentromeric heterochromatin primarily through its H3K14ub-binding activity. Notably, loss of G2E3 severely impairs pericentromeric heterochromatin organization and results in the aberrant accumulation of SUV39H and H3K9me3 in numerous euchromatin regions and widespread transcriptional repression. Thus, our findings revealed the H3K14ub-dependent SUV39H compartmentalization as a unified mechanism of pericentromeric heterochromatin formation, which is essential for proper euchromatin compartmentalization and transcriptional regulation.

DOI: 10.1038/s41586-025-09624-5

Source: https://www.nature.com/articles/s41586-025-09624-5