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^BAH) ‘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^BAH, 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^BAH–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’.

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。^{我们报告了 BAHCC1 (BAHCC1 BAH} ) 的保守溴邻同源性 (BAH) 模块特异性“识别”H3K27me3 并在哺乳动物细胞中强制沉默 H3K27me3 分界基因。^{基于生化、结构和整合染色质免疫沉淀测序的分析表明，BAHCC1 对 H3K27me3 的直接读出是通过 BAHCC1 BAH}形成的疏水性三甲基-l-赖氨酸结合“笼”实现的, 介导 BAHCC1 和 H3K27me3 标记基因的共定位。BAHCC1 在人类急性白血病中高表达，并与转录辅助抑制因子相互作用。在白血病中，BAHCC1 的耗竭或 BAHCC1 ^BAH –H3K27me3 相互作用的破坏会导致参与肿瘤抑制和细胞分化的 H3K27me3 靶向基因的去阻遏，从而抑制肿瘤发生。在小鼠中，在Bahcc1处引入种系突变以破坏其 H3K27me3 结合会导致部分出生后致死率，从而支持其在发育中的作用。这项研究确定了哺乳动物中 H3K27me3 定向转导途径，该途径依赖于保守的 BAH“阅读器”。