ASB7 is a negative regulator of H3K9me3 homeostasis
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
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.