Diffuse midline gliomas and posterior fossa type A ependymomas contain the recurrent histone H3 lysine 27 (H3 K27M) mutation and express the H3 K27M-mimic EZHIP (CXorf67), respectively. H3 K27M and EZHIP are competitive inhibitors of Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase activity. In vivo, these proteins reduce overall H3 lysine 27 trimethylation (H3K27me3) levels; however, residual peaks of H3K27me3 remain at CpG islands (CGIs) through an unknown mechanism. Here, we report that EZHIP and H3 K27M preferentially interact with PRC2 that is allosterically activated by H3K27me3 at CGIs and impede its spreading. Moreover, H3 K27M oncohistones reduce H3K27me3 in trans, independent of their incorporation into the chromatin. Although EZHIP is not found outside placental mammals, expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved mechanism. Our results provide mechanistic insights for the retention of residual H3K27me3 in tumors driven by H3 K27M and EZHIP.

弥漫性中线胶质瘤和后颅窝 A 型室管膜瘤分别含有复发性组蛋白 H3 赖氨酸 27 (H3 K27M) 突变并表达 H3 K27M 模拟 EZHIP (CXorf67)。H3 K27M 和 EZHIP 是 Polycomb Repressive Complex 2 (PRC2) 赖氨酸甲基转移酶活性的竞争性抑制剂。在体内，这些蛋白质降低了 H3 赖氨酸 27 三甲基化 (H3K27me3) 的总体水平；然而，H3K27me3 的残留峰通过未知机制保留在 CpG 岛 (CGI) 上。在这里，我们报告EZHIP和H3 K27M优先与在CGI处被H3K27me3变构激活的PRC2相互作用并阻碍其传播。此外，H3 K27M 癌组蛋白以反式形式减少 H3K27me3 ，与它们是否掺入染色质无关。尽管在胎盘哺乳动物之外未发现 EZHIP，但人 EZHIP 的表达通过保守机制降低果蝇中的 H3K27me3。我们的结果为 H3 K27M 和 EZHIP 驱动的肿瘤中残留的 H3K27me3 保留提供了机制见解。