Variant and cell-context specific H3K27M reprogramming results in distinct enhancer architecture and oncogenic states

Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique lysine-to-methionine substitution in histone-3 at lysine 27 (H3K27M). We show here that the specific Polycomb targets disrupted by H3K27M and resultant oncogenic state is dependent on both the variant of histone-3 and the cell- context in which the mutation occurs. Through primary DIPG tumor characterization and isogenic expression, we show that the same H3K27M mutation displays distinct modes of oncogenic reprogramming and establishes distinct enhancer architecture depending on whether it occurs in genes encoding H3.3 or H3.1. By comparison to non-malignant pediatric pontine tissue, we create a molecular map for DIPG, identifying and functionally validating both shared and subgroup-specific pathophysiology. Directly comparing the earliest events of H3K27M tumor initiation in putative cells-of-origin demonstrates that DIPG arises only from an oligodendrocyte precursor cell state.

弥漫内生型桥脑胶质瘤（Diffuse intrinsic pontine glioma, DIPG）是一种儿童致死性桥脑恶性肿瘤，其标志性特征为组蛋白H3第27位赖氨酸发生赖氨酸至甲硫氨酸的特异性替换突变（H3K27M）。本研究表明，由H3K27M突变及由此产生的致癌状态所干扰的特异性多梳（Polycomb）靶标，同时取决于组蛋白H3的变体类型与突变发生的细胞背景。通过对原发性DIPG肿瘤的特征分析与同基因表达系统验证，我们发现同一H3K27M突变可呈现不同的致癌重编程模式，并会根据突变发生于编码H3.3还是H3.1的基因，构建出截然不同的增强子架构。与非恶性儿童桥脑组织进行比对后，我们构建了DIPG的分子图谱，鉴定并功能验证了该肿瘤共有的及亚群特异性的病理生理机制。直接比对推测的肿瘤起源细胞中H3K27M突变介导的肿瘤起始早期事件后证实，DIPG仅起源于少突胶质前体细胞（oligodendrocyte precursor cell）状态。