原神经胶质瘤是一种脑肿瘤，其特征是少突胶质细胞祖细胞（OPC）转录物的富集和遗传改变。在本研究中，我们试图鉴定具有 Trp53 缺失和 PDGF-BB 过表达 (BB-p53n) 的 OPC 与仅携带 p53 缺失 (p53n) 的 OPC 之间的转录和表观遗传差异。在培养中，BB-p53n OPC 显示出比 p53n OPC 更类似于神经胶质瘤细胞的生长特征。当注射到小鼠大脑中时，BB-p53n OPC 会形成肿瘤，而 p53n OPC 则不会。对这些 OPC 群体进行无偏的组蛋白蛋白质组学和转录组学分析，发现组蛋白 H3K27me3 标记水平较高，而组蛋白 H4K20me3 水平较低。与 p53n OPC 相比，BB-p53n OPC 的转录组的特点是与增殖和细胞粘附相关的转录物水平更高。对 BB-p53n OPC 中负责组蛋白 H3K27 三甲基化 (EZH2i) 的酶进行药理学抑制，可减少细胞周期转录并增加分化标记物的表达，但不足以恢复其生长特性。这表明 p53n OPC 中的 PDGF-BB 过表达有利于转化的早期阶段，通过 H3K27me3 依赖性途径促进增殖和停止分化，并以 H3K27me3 独立方式有利于生长特征。版权所有 © 2024。由 Elsevier Inc. 出版。

Proneural gliomas are brain tumors characterized by enrichment of oligodendrocyte progenitor cell (OPC) transcripts and genetic alterations. In this study we sought to identify transcriptional and epigenetic differences between OPCs with Trp53 deletion and PDGF-BB overexpression (BB-p53n) and those carrying only p53 deletion (p53n). In culture, the BB-p53n OPCs display growth characteristics more similar to glioma cells than p53n OPCs. When injected in mouse brains, BB-p53n OPC form tumors, while the p53n OPCs do not. Unbiased histone proteomics and transcriptomic analysis on these OPC populations identified higher levels of the histone H3K27me3 mark and lower levels of the histone H4K20me3. The transcriptome of the BB-p53n OPCs was characterized by higher levels of transcripts related to proliferation and cell adhesion compared to p53n OPCs. Pharmacological inhibition of the enzyme responsible for histone H3K27 trimethylation (EZH2i) in BB-p53n OPCs, reduced cell cycle transcripts and increased the expression of differentiation markers, but was not sufficient to restore their growth characteristics. This suggests that PDGF-BB overexpression in p53n OPCs favors the early stages of transformation, by promoting proliferation and halting differentiation in a H3K27me3-dependent pathway, and favoring growth characteristics in a H3K27me3 independent manner.Copyright © 2024. Published by Elsevier Inc.