Understanding the Mechanisms of Gliomagenesis in Oligodendrocyte Progenitors, Driven by Trp53 Loss and Idh1 Mutation
Dennis Huang1,2,3,4, Angeliki Mela5, Peter Canoll5, Konstantino Krampis1,2,4, Patrizia Casaccia1,3.
1The Graduate Center, City University of New York
2Belfer Research Institute, City University of New York & Weill Cornell Medical College
3Neuroscience Initiative, Advance Science Research Center, City University of New York
4Department of Biological Sciences, Hunter College, City University of New York
5Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
Gliomas are the most common and lethal tumors of the adult brain. Through the combination of large scale transcriptional and genome-wide associative studies, this cancer has been classified into several subtypes, characterized by distinct mutations and expression signatures. One such subtype of interest is proneural glioma, characterized by increased PDGFRα signaling, loss of TP53, and IDH1 mutation. PDGFRα is a well-established marker of oligodendrocyte progenitors (OPCs), the precursors to myelinating oligodendrocytes of the central nervous system and largest body of proliferating cells in the adult brain. Follow up studies have shown tumors formed from mutated OPCs observed in vivo. The mechanisms which drive tumorigenesis in OPCs are poorly understood but could be elucidated by investigations toward the intrinsic epigenetic landscape of tumorigenic cells. Both the lineage and differentiation process of oligodendrocytes depends on specific changes in the epigenome, mediated by histone and DNA methylation. In addition, previous studies and preliminary results suggest that the mutations found in proneural glioma (TP53 loss, IDH1 mutation) alter repressive histone modifications in different ways. This preliminary finding supports the hypothesis of the epigenome as a driving force of tumorigenesis. This project aims to answer key questions about the epigenetically driven mechanisms in OPCs leading to transformation in a well-established glioma model in mice by utilizing advanced sequencing techniques. ChIP-seq will characterize the genomic distribution of expression regulating histone marks in mutant OPCs harboring Trp53 deletion and Idh1 mutant expression. Single cell multiomics will characterize both chromatin accessibility and gene expression in tumor tissue at single cell resolution. These data may lead to better understanding of the transforming cell population in early proneural glioma and better therapeutic strategies which target genome-wide drivers of gliomagenesis.
