Program in Molecular, Cellular and Developmental Biology at The Graduate Center of The City University of New, York 365 5th Ave, New York, NY 10016, United States; Belfer Research Institute, City University of New York & Weill Cornell Medical College, 413 E 69th St, New York, NY 10021, United States; Neuroscience Initiative, Advance Science Research Center, Graduate Center of The City University of New York, 85 St Nicholas Terrace, New York, NY 10031, United States; Department of Biological Sciences, Hunter College, City University of New York, 695 Park Ave, New York, NY 10065, United States.
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 622 W 168th St, New York, NY 10032, United States.
Neoplasia. 2024 Nov;57:101042. doi: 10.1016/j.neo.2024.101042. Epub 2024 Aug 30.
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.
神经前体细胞胶质瘤是一种脑肿瘤，其特征是少突胶质前体细胞（OPC）转录本的富集和遗传改变。在这项研究中，我们试图确定 Trp53 缺失和 PDGF-BB 过表达（BB-p53n）的 OPC 与仅携带 p53 缺失（p53n）的 OPC 之间的转录组和表观遗传差异。在培养中，BB-p53n OPC 显示的生长特征比 p53n OPC 更类似于神经胶质瘤细胞。当将 BB-p53n OPC 注入小鼠大脑时，它们形成肿瘤，而 p53n OPC 则不会。对这些 OPC 群体进行无偏倚的组蛋白蛋白质组学和转录组学分析，发现组蛋白 H3K27me3 标记的水平更高，而组蛋白 H4K20me3 的水平更低。与 p53n OPC 相比，BB-p53n OPC 的转录组特征是与增殖和细胞黏附相关的转录本水平更高。在 BB-p53n OPC 中，负责组蛋白 H3K27 三甲基化的酶（EZH2i）的药理抑制，降低了细胞周期转录本并增加了分化标记物的表达，但不足以恢复其生长特征。这表明，p53n OPC 中的 PDGF-BB 过表达通过促进增殖和依赖 H3K27me3 途径阻止分化，从而有利于转化的早期阶段，并且以不依赖于 H3K27me3 的方式有利于生长特征。
