Single-nucleus transcriptomics identifies dysregulation of cell cycle control and synaptic pathways during the progression of murine proneural gliomas.

Here, we injected in vitro transformed OPCs (with Trp53 deletion and PDGF-BB overexpression, (BB-p53n) into the subcortical white matter of syngeneic mice, and then performed single-nucleus RNA sequencing on brain samples isolated from the murine brains at early and late time points in order to study the transcriptional changes occurring during the progression from early- to late-stage gliomas. Compared to normal brain, the early- and late- stage samples were characterized by clusters of cells bearing an “OPC-like” transcriptional phenotype. These cells expressed high levels of OPC genes, including Pdgfra and Olig2, but also expressed genes that are frequently upregulated in glioma cells, including Sox2, Nestin and CD44. Compared to early-stage tumor samples, late-stage glioma samples were characterized by the expansion of cells with a transcriptional signature enriched in genes regulating cell cycle and synaptic assembly. Pseudo-time analysis of the early and late samples identified a trajectory of decreasing cell cycle checkpoint regulation and increasing synaptic signaling. Together these data suggest that the progression from transformed OPCs to proneural gliomas includes transcriptional changes that favor proliferation and interactions with neurons. Overall design: Gliomas were induced in normal mouse brains by the injection of tumorigenic BB-p53n OPCs. Tumors were removed at early- and late-stages and processed for 10X snRNA-seq 3' Gene expression