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.

Public Health Relevance

Gliomas are an extremely devastating, incurable and highly prevalent adult brain tumors and oligodendrocyte progenitors have been proposed as cell-of-origin for proneural gliomas. This proposal investigates the role and regulation of PRMT5, an enzyme which is enriched in the oligodendrocyte progenitors and amplified in gliomas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052738-14
Application #
10016389
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2017-09-01
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
14
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Advanced Science Research Center
Department
Type
Organized Research Units
DUNS #
831361857
City
New York
State
NY
Country
United States
Zip Code
10031
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Moyon, Sarah; Ma, Dan; Huynh, Jimmy L et al. (2017) Efficient Remyelination Requires DNA Methylation. eNeuro 4:
Moyon, Sarah; Casaccia, Patrizia (2017) DNA methylation in oligodendroglial cells during developmental myelination and in disease. Neurogenesis (Austin) 4:e1270381
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Liu, Jia; Moyon, Sarah; Hernandez, Marylens et al. (2016) Epigenetic control of oligodendrocyte development: adding new players to old keepers. Curr Opin Neurobiol 39:133-8
Moyon, Sarah; Liang, Jialiang; Casaccia, Patrizia (2016) Epigenetics in NG2 glia cells. Brain Res 1638:183-198
Gacias, Mar; Gaspari, Sevasti; Santos, Patricia-Mae G et al. (2016) Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. Elife 5:
Hernandez, Marylens; Patzig, Julia; Mayoral, Sonia R et al. (2016) Mechanostimulation Promotes Nuclear and Epigenetic Changes in Oligodendrocytes. J Neurosci 36:806-13
Moyon, Sarah; Huynh, Jimmy L; Dutta, Dipankar et al. (2016) Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage. Cell Rep 15:748-760

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