Mechanism of regulation of progenitor proliferation and transformation

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Glioblastomas (GBM) are highly aggressive and incurable primary brain tumors, with a median survival of little more than a year. Expression profiling and whole genome sequencing from hundreds of human glioma specimens have revealed a broad spectrum of genetic alterations and identified four major expression signatures, including a pattern of expression that is highly enriched in oligodendrocyte lineage genes, which is also characterized by mutations in the tumor suppressor p53. During the previous funding period we focused on the molecular mechanisms regulating proliferation and gene expression in oligodendrocyte progenitor cells, with an emphasis on E2F1 and Myc as transcription factors and recruiters of epigenetic modulators of lysine residues on nucleosomal histone H3. This renewal focuses on a novel histone modification (symmetric arginine methylation catalyzed by PRMT5), which we define as critical for oligodendrocyte progenitor (OPC) differentiation. Since PRMT5 is upregulated in glioma, and its expression levels negatively correlate with patients' survival, it represents a very attractive therapeutic target. Based on our proteomic and transcriptomic datasets we propose that a better understanding of its molecular mechanism of action would shed important light on mechanisms of OPC differentiation in physiological conditions and of transformation into proneural gliomas. We anticipate that the results of the proposed experimental plan will enhance the current knowledge of OPC population dynamic, while impacting a better understanding of the process of glial transformation and suggesting novel therapeutic targets. The overall goal is to characterize PRMT5 molecular partners and mechanism of action in normal OPCs under physiological conditions and in transformed OPCs at different stages of glioma progression, address its function in the presence or absence of p53 and evaluate the potential therapeutic value of PRMT5 inhibition in gliomas.