ASB7 is a negative regulator of H3K9me3 homeostasis

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-05-29 DOI:10.1126/science.adq7408

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

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引用次数: 0

Abstract

The maintenance of histone H3 lysine 9 trimethylation (H3K9me3) involves the recognition of preexisting modifications by heterochromatin protein 1 (HP1), which recruits the methyltransferase suppressor of variegation 3-9 homolog 1 (SUV39H1) to methylate the adjacent newly incorporated histones, establishing a positive feedback loop. However, how this positive feedback is restricted to maintain H3K9me3 homeostasis remains largely unknown. We performed an unbiased genome-scale CRISPR-Cas9 screen and identified CUL5^ASB7 E3 ubiquitin ligase as a negative regulator of H3K9me3. ASB7 is recruited to heterochromatin by HP1 and promotes SUV39H1 degradation. During mitosis, cyclin-dependent kinase 1 (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, ensuring faithful epigenetic inheritance and preventing excessive heterochromatin formation.

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ASB7是H3K9me3稳态的负调节因子。

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。在这里，我们进行了无偏倚的基因组级CRISPR-Cas9筛选，并鉴定出CUL5ASB7 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。我们的研究结果揭示了一个涉及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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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