BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis

Huitao Fan, Jiuwei Lu, Yiran Guo, Dongxu Li, Zhi Min Zhang, Yi Hsuan Tsai, Wen Chieh Pi, Jeong Hyun Ahn, Weida Gong, Yu Xiang, David F. Allison, Huimin Geng, Shenghui He, Yarui Diao, Wei Yi Chen, Brian D. Strahl, Ling Cai, Jikui Song, Gang Greg Wang*

*此作品的通信作者

研究成果: Article同行評審

46 引文 斯高帕斯(Scopus)

摘要

Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) ‘recognizes’ H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses demonstrate that direct readout of H3K27me3 by BAHCC1 is achieved through a hydrophobic trimethyl-l-lysine-binding ‘cage’ formed by BAHCC1BAH, mediating colocalization of BAHCC1 and H3K27me3-marked genes. BAHCC1 is highly expressed in human acute leukemia and interacts with transcriptional corepressors. In leukemia, depletion of BAHCC1, or disruption of the BAHCC1BAH–H3K27me3 interaction, causes derepression of H3K27me3-targeted genes that are involved in tumor suppression and cell differentiation, leading to suppression of oncogenesis. In mice, introduction of a germline mutation at Bahcc1 to disrupt its H3K27me3 engagement causes partial postnatal lethality, supporting a role in development. This study identifies an H3K27me3-directed transduction pathway in mammals that relies on a conserved BAH ‘reader’.

原文English
頁(從 - 到)1384-1396
頁數13
期刊Nature Genetics
52
發行號12
DOIs
出版狀態Published - 12月 2020

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