A specific form of cPRC1 containing CBX4 is co-opted to mediate oncogenic gene repression in diffuse midline glioma

Diffuse midline glioma (DMG) is a fatal childhood brain tumour characterised primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3. Paradoxically, PRC2 is essential in DMG cells, although the downstream molecular mechanisms are poorly understood. Here, we’ve discovered a specific form of canonical PRC1 (cPRC1) containing CBX4 and PCGF4 drives oncogenic gene repression downstream of H3K27me3 in DMG cells. Via a novel functional region, CBX4 preferentially associates with PCGF4 containing cPRC1. The characteristic H3K27me3 landscape in DMG rewires the distribution of cPRC1 complexes, with CBX4/PCGF4-cPRC1 accumulating at H3K27me3 enriched CpG islands. Despite comprising <5% of cPRC1 in DMG cells, the unique repressive functions of CBX4/PCGF4-cPRC1 are essential for DMG growth. Our findings link the altered distribution of H3K27me3 to imbalanced cPRC1 function, which drives oncogenic gene repression in DMG, highlighting potential therapeutic opportunities for this incurable childhood brain cancer.

弥漫性中线胶质瘤（Diffuse midline glioma, DMG）是一种致命的儿童脑肿瘤，核心特征为突变组蛋白H3（H3K27M）的存在。H3K27M会导致多梳抑制复合体2（Polycomb Repressive Complex 2, PRC2）介导的组蛋白H3赖氨酸27三甲基化（H3K27me3）水平全面降低。令人矛盾的是，PRC2在DMG细胞中却是必需的，但其下游分子机制尚不甚明确。本研究发现，一种包含CBX4与PCGF4的特异性经典多梳抑制复合体1（canonical PRC1, cPRC1），可在DMG细胞中介导H3K27me3下游的致癌基因阻遏。通过一段全新的功能区域，CBX4优先与含PCGF4的cPRC1相结合。DMG细胞中特有的H3K27me3分布景观会重编程cPRC1复合物的分布，使CBX4/PCGF4-cPRC1富集于H3K27me3富集的CpG岛。尽管该复合物在DMG细胞的cPRC1中占比不足5%，但其独特的阻遏功能对DMG的生长至关重要。本研究将H3K27me3分布改变与失衡的cPRC1功能联系起来，后者可介导DMG中的致癌基因阻遏，为这种无法治愈的儿童脑癌凸显了潜在的治疗机遇。