中山大学康铁邦研究组近日取得一项新成果。经过不懈努力，他们开发出ASB7是H3K9me3稳态的负调节因子。这一研究成果于2025年5月29日发表在国际顶尖学术期刊《科学》上。

研究团队进行了无偏倚的基因组级CRISPR-Cas9筛选，发现CUL5^ASB7 E3泛素连接酶是H3K9me3的负调节因子。ASB7被HP1募集到异染色质上，促进SUV39H1的降解。在有丝分裂过程中，CDK1磷酸化ASB7，阻止其与SUV39H1的相互作用，导致SUV39H1稳定和H3K9me3恢复。他们的发现揭示了一个涉及HP1、SUV39H1和ASB7的动态电路，该电路控制H3K9me3的内稳态，从而确保忠实的表观遗传并防止过多的异染色质形成。

据介绍，H3K9me3的维持涉及HP1对先前存在的修饰的识别，HP1招募甲基转移酶SUV39H1将相邻的新纳入的组蛋白甲基化，从而建立一个正反馈循环。然而，这种正反馈是如何被限制以维持H3K9me3体内平衡的，在很大程度上仍然是未知的。

附：英文原文

Title: ASB7 is a negative regulator of H3K9me3 homeostasis

Author: Liwen Zhou, Zhenxuan Chen, Yezi Zou, Xia Zhang, Zifeng Wang, Hongwen Zhu, Jiahui Lin, Ziyao Huang, Lisi Zheng, Jiali Chen, Miner Xie, Meifang Zhang, Ruhua Zhang, Minglu Zhu, Ziwen Wang, Hu Zhou, Song Gao, Yuxin Yin, Yuanzhong Wu, Tiebang Kang

Issue&Volume: 2025-05-29

Abstract: The maintenance of H3K9me3 involves the recognition of pre-existing modifications by HP1, which recruits methyltransferase SUV39H1 to methylate the adjacent newly incorporated histones, thereby establishing a positive feedback loop. However, how this positive feedback is restricted to maintain H3K9me3 homeostasis remains largely unknown. Here, we performed an unbiased genome-scale CRISPR-Cas9 screen and identified CUL5ASB7 E3 ubiquitin ligase as a negative regulator of H3K9me3. ASB7 is recruited to heterochromatin by HP1 and promotes SUV39H1 degradation. During mitosis, CDK1 phosphorylates ASB7, preventing its interaction with SUV39H1, leading to SUV39H1 stabilization and H3K9me3 restoration. Our findings reveal a dynamic circuit involving HP1, SUV39H1, and ASB7 that governs H3K9me3 homeostasis, thereby ensuring faithful epigenetic inheritance and preventing excessive heterochromatin formation.

DOI: adq7408

Source: https://www.science.org/doi/10.1126/science.adq7408