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BAHCC1 通过一个保守的 BAH 模块结合 H3K27me3 来介导基因沉默和致癌作用。

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

机构信息

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.

出版信息

Nat Genet. 2020 Dec;52(12):1384-1396. doi: 10.1038/s41588-020-00729-3. Epub 2020 Nov 2.

DOI:10.1038/s41588-020-00729-3
PMID:33139953
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8330957/
Abstract

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 (BAHCC1) '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 BAHCC1, 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 BAHCC1-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'.

摘要

三甲基化组蛋白 H3 赖氨酸 27（H3K27me3）调节基因抑制、细胞命运决定和分化。我们报告说，BAHCC1（BAHCC1）的一个保守溴相邻同源（BAH）模块“识别”H3K27me3 特异性，并在哺乳动物细胞中强制沉默 H3K27me3 标记的基因。生化、结构和整合染色质免疫沉淀测序分析表明，BAHCC1 通过 BAHCC1 形成的疏水性三甲基-L-赖氨酸结合“笼”直接读取 H3K27me3，介导 BAHCC1 和 H3K27me3 标记基因的共定位。BAHCC1 在人类急性白血病中高度表达，并与转录共抑制因子相互作用。在白血病中，BAHCC1 的耗竭或 BAHCC1-H3K27me3 相互作用的破坏导致 H3K27me3 靶向基因的去抑制，这些基因参与肿瘤抑制和细胞分化，导致致癌作用的抑制。在小鼠中，引入 Bahcc1 的种系突变以破坏其 H3K27me3 结合导致部分出生后致死，支持其在发育中的作用。本研究鉴定了哺乳动物中依赖于保守 BAH“读取器”的 H3K27me3 定向转导途径。

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