Science Bulletin, 19 January, 2026, DOI：https://doi.org/10.1016/j.scib.2026.01.039
Histone H3.3 phosphorylation facilitates H3K9me3-heterochromatin formation during retrotransposon silencing and X-chromosome inactivation via H3.3K27me3–CBX7–KAP1 axis
Jun Chen, Jiyu Chen, Zhouliang Yu, Liwei Zhang, Yanchao Liu, Xuan Ouyang, Juan Yu, Menghan Wang, Shangqiang Xie, Ming Wang, Tiantian Zhang, Zhaohui Jin, Bin Wu, Li Huang, Zijuan Gu, Lin Liu, Bing Zhu, Ping Chen, Haiyan Lin, Jicheng Zhao, Sheng Ye, Aiwu Dong, Yang Yu, Ying Huang, Guohong Li
Abstract
The conserved histone variant H3.3 plays pivotal roles in heterochromatin formation and retrotransposon silencing. However, the molecular mechanism underlying H3.3-primed heterochromatin regulation remains elusive. Here, we demonstrate that H3.3-specific Ser31 phosphorylation and Lys27 trimethylation synergistically promote H3K9me3-heterochromatin formation. Mechanistically, polycomb protein chromobox homolog 7 (CBX7) preferentially binds Ser31-phosphorylated H3.3K27me3 nucleosomes and then recruits KRAB-associated protein 1 (KAP1), which may further engage the histone lysine 9 methyltransferase to establish H3K9me3-associated heterochromatin. Remarkably, H3K9me3 is significantly impaired when the H3.3–CBX7 interaction is disrupted, accompanied by the activation of retrotransposons. Moreover, during X-chromosome inactivation (XCI), H3K9me2/3 fails to accumulate at the inactive X (Xi) when blocking the H3.3–CBX7–KAP1 axis. Taken together, our results reveal a novel molecular mechanism by which H3.3 Ser31 phosphorylation (H3.3Ser31p) facilitates H3K9me3-heterochromatin formation during retrotransposon silencing and XCI via the H3.3K27me3–CBX7–KAP1 axis.
文章链接：https://www.sciencedirect.com/science/article/pii/S2095927326000460?via%3Dihub
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