ABSTRACT The polycomb repressive complex 2 (PRC2) is recurrently disrupted in brain cancer; a complex required for depositing the repressive histone modification, H3K27 tri-methylation (H3K27me3). Maintenance of PRC2 function is important for repression of genes and repetitive elements, providing a safe-guard against aberrant transcription. PRC2 is essential for proper embryonic cell maintenance, neural stem cell differentiation, and overall brain development. How PRC2 dysfunction and aberrant H3K27me3 levels contributes to brain tumorigenesis is unclear. As a model of PRC2 dysfunction in brain tumors, our lab investigates midline high grade gliomas (HGG) that harbor frequent histone H3 lysine 27 to methionine mutations (denoted H3K27M). Expression of H3K27M impairs PRC2 function and results in a global loss of H3K27me3; a defining feature of these brain tumors. Using isogenic glioma models in which H3K27M is deleted, we found that the H3K27M results in a global increase in a mark of active transcription, H3K27 acetylation (H3K27ac) (Krug et al., Cancer Cell, 2019). Surprisingly, global H3K27ac has minimal effects on gene transcription. Instead, we discovered a novel mechanism of H3K27ac associated transcription of repetitive DNA elements, namely Type-H human endogenous retroviral (HERV) sequences. We hypothesize that: 1) HERV activation plays a functional role in the biology of H3K27M-driven glioma, and 2) Amplification of HERV expression represents a novel anti-cancer strategy against tumors with global loss of H3K27me3. To test this hypothesis we propose three specific aims to: 1) Decipher the mechanisms of HERV transcriptional activation in H3K27M-driven glioma, 2) Determine the impact of HERV expression on H3K27M-glioma cell identity and tumor formation, and 3) Delineate the mechanisms of HERV detection and response in H3K27M-glioma. Collectively these experiments will reveal mechanistic insight into the role of HERV expression in high-grade glioma and cellular vulnerabilities created by H3K27M mutations.