一种含有CBX4的特定形式的cPRC1被用于介导弥漫性中线胶质瘤中的致癌基因抑制。 - Suppr | 超能文献

Abstract

Diffuse midline glioma (DMG) is a fatal childhood brain tumor characterized primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3). Paradoxically, PRC2 is essential in DMG cells, although the downstream molecular mechanisms are poorly understood. Here, we have discovered a specific form of canonical PRC1 (cPRC1) containing CBX4 and PCGF4 that 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.

摘要

弥漫性中线胶质瘤（DMG）是一种致命的儿童脑肿瘤，主要特征是突变的组蛋白H3（H3K27M）。H3K27M导致多梳抑制复合物2（PRC2）介导的H3K27三甲基化（H3K27me3）整体减少。矛盾的是，PRC2在DMG细胞中至关重要，尽管其下游分子机制尚不清楚。在这里，我们发现了一种包含CBX4和PCGF4的典型PRC1（cPRC1）的特定形式，它在DMG细胞中驱动H3K27me3下游的致癌基因抑制。通过一个新的功能区域，CBX4优先与含PCGF4的cPRC1结合。DMG中特征性的H3K27me3景观重塑了cPRC1复合物的分布，CBX4/PCGF4-cPRC1在富含H3K27me3的CpG岛处积累。尽管在DMG细胞中CBX4/PCGF4-cPRC1占cPRC1的比例不到5%，但其独特的抑制功能对DMG的生长至关重要。我们的研究结果将H3K27me3分布的改变与cPRC1功能失衡联系起来，后者驱动了DMG中的致癌基因抑制，突出了这种无法治愈的儿童脑癌潜在的治疗机会。