2. Academic Validation
  3. A conserved H3K14ub-driven H3K9me3 for chromatin compartmentalization

A conserved H3K14ub-driven H3K9me3 for chromatin compartmentalization

  • Nature. 2025 Oct 15. doi: 10.1038/s41586-025-09624-5.
Yuanyong Huang # 1 2 3,  Yimei Sun # 2,  Hongyun Qi # 4,  Quanlong Jiang # 5,  Jialun Li 2,  Mingzhi Chang 2,  Xinyan Li 2,  Lei Shu 2,  Xiaoya Duan 2,  Yiqin Wang 4,  Kailun Fang 4,  Hailei Mao 4,  Mengmeng Han 2,  Yuan Weng 2,  Qiao Zhang 2,  Zhaosu Chen 2,  Wei Wei 2,  Gaojie Song 2,  Qiansen Zhang 2,  Jiwen Li 2,  Jing-Dong J Han 6,  Charlie Degui Chen 7,  Jiemin Wong 8 9 10
Affiliations

Affiliations

  • 1 WuHu Hospital, East China Normal University (The Second People's Hospital of WuHu), Wuhu, China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
  • 3 Joint Center for Translational Medicine, Fengxian District Central Hospital, Shanghai, China.
  • 4 State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 5 Medical Research Center, Nantong First People's Hospital, Nantong, People's Republic of China.
  • 6 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, China.
  • 7 State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. cdchen@sibcb.ac.cn.
  • 8 WuHu Hospital, East China Normal University (The Second People's Hospital of WuHu), Wuhu, China. jmweng@bio.ecnu.edu.cn.
  • 9 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. jmweng@bio.ecnu.edu.cn.
  • 10 Joint Center for Translational Medicine, Fengxian District Central Hospital, Shanghai, China. jmweng@bio.ecnu.edu.cn.
  • # Contributed equally.
PMID: 41094145 DOI: 10.1038/s41586-025-09624-5
Abstract

Compartmentalization of eukaryotic genome into euchromatin and heterochromatin is of critical biological significance1-3. 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.

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