美国国立卫生研究院Shiv I. S. Grewal团队的一项最新研究探明了应激通过组蛋白H3泛素化控制异染色质遗传。这一研究成果于2026年1月7日发表在国际顶尖学术期刊《自然》上。

在这里，该研究组发现了一个泛素依赖的异染色质遗传力调控中心（HRH），它广泛地控制着异染色质的繁殖，即使没有组蛋白去乙酰化酶的活性。HRH由限制因子Raf1^DDB2调节，Raf1^DDB2是ClrC泛素连接酶的底物受体。除了将Clr4SUV39H连接到染色质上的其他ClrC成分外，Raf1DDB2还以剂量依赖的方式促进赖氨酸14处组蛋白H3的泛素化（H3K14ub），这对异染色质自增殖至关重要。

HRH与环境响应途径有着复杂的联系，包括无意义介导的衰变（NMD）和雷帕霉素靶（TOR）信号传导，使细胞能够适应不断变化的条件。通过调节异染色质繁殖，细胞利用HRH获得抗真菌剂的抗性并适应高温。因此，异染色质自繁殖是通过H3K14ub响应外部刺激而积极调节的，这对于理解生理和疾病中表观遗传景观快速变化的机制具有广泛的意义。

据介绍，以组蛋白H3赖氨酸9甲基化为标志的异染色质可以通过细胞分裂进行表观遗传遗传，维持基因抑制，从而保持细胞身份并使其能够适应环境挑战。对粟酒裂殖酵母的研究表明，异染色质的繁殖依赖于读写机制，其中足够密度的H3K9me3修饰核小体，通过组蛋白去乙酰化酶稳定，将Clr4^SUV39H集中在染色质上，促进H3K9甲基化的进一步沉积。是否还有其他机制通过E3泛素连接酶复合物ClrC的一个亚基Clr4^SUV39H控制异染色质的繁殖尚不清楚。

附：英文原文

Title: Stress controls heterochromatin inheritance via histone H3 ubiquitylation

Author: Bhatt, Bharat, Wei, Yi, Pradhan, Ashis Kumar, Dhakshnamoorthy, Jothy, Zofall, Martin, Xiao, Hua, Vijayakumari, Drisya, Jain, Shweta, Folco, Hernan Diego, Qi, Hongyun, Ball, David A., Karpova, Tatiana S., Wheeler, David, Wong, Jiemin, Grewal, Shiv I. S.

Issue&Volume: 2026-01-07

Abstract: Heterochromatin, marked by histone H3 lysine 9 methylation, can be epigenetically inherited through cell division1,2,3, maintaining gene repression that preserves cell identity and enables adaptation to environmental challenges2,3,4,5,6. Studies on Schizosaccharomyces pombe have shown that heterochromatin propagation depends on the read–write mechanism, wherein a sufficient density of H3K9me3-modified nucleosomes, stabilized by histone deacetylases, concentrates Clr4SUV39H on chromatin to promote further deposition of H3K9 methylation7,8,9. Whether other mechanisms control heterochromatin propagation by means of Clr4SUV39H, a subunit of the E3 ubiquitin ligase complex ClrC10,11,12, was unknown. Here we uncover a ubiquitin-dependent heterochromatin heritability regulatory hub (HRH) that broadly governs heterochromatin propagation, even without histone deacetylase activity. The HRH is tuned by the limiting factor Raf1DDB2, a substrate receptor for the ClrC ubiquitin ligase. In addition to linking Clr4SUV39H to other ClrC components on chromatin, Raf1DDB2 acts in a dosage-dependent manner to promote ubiquitination of histone H3 at lysine 14 (H3K14ub), which is critical for heterochromatin self-propagation. HRH is intricately linked to environmentally responsive pathways, including nonsense-mediated decay (NMD) and target of rapamycin (TOR) signalling, enabling cells to adapt to changing conditions. By modulating heterochromatin propagation, cells leverage the HRH to gain resistance to antifungal agents and adapt to high temperature. Thus, heterochromatin self-propagation is actively regulated by means of H3K14ub in response to external stimuli, with broad implications for understanding mechanisms governing rapid changes in the epigenetic landscape in physiology and disease.

DOI: 10.1038/s41586-025-09899-8

Source: https://www.nature.com/articles/s41586-025-09899-8