Abstract
Abstract IDH1-wildtype (WT) GBMs are the most common and aggressive tumors of the central nervous system (CNS), with a median survival rate of 12-15 months, and are resistant to clinical therapies due to their heterogenous molecular phenotype. In this study, we developed a pipeline to dissect the potential role of human endogenous retroviruses (HERVs) in patient derived glioma stem cells (GSCs) and integrated our findings with published epigenomic datasets for enhancers (H3K27ac), CTCF, and chromatin toplogy (Hi-C). We found high expression of several HERV transcripts in IDH1-WT GBMs as compared to IDH1-mutant variants. Epigenomic analysis of these upregulated HERVs showed association with both enhancer marks and CTCF deposition. Annotation of HERVs to their nearest genes, followed by Gene Set Enrichment Analysis (GSEA), identified involvement of actin-filament based mechanisms and regulation of immune phenotype. Integration of these findings identified MER61 (ERVMER61-1), a potential regulator of Interleukin-6 and showed alteration in chromatin looping and enhancer occupancy. To summarize, our work points to novel mechanisms of GBM pathogenesis, through involvement of HERVs in cell migratory and immune dysfunction, warranting further investigations into these oncogenic mechanism to identify and develop novel therapeutic options for GBM.
Published Version
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