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A methionine substitution at lysine-27 on histone H3 variants (H3K27M) is present in more than 80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. We discovered that a number of parameters were involved in H3K27M-dependent inhibition of PRC2, including the ratio between H3K27M and PRC2 present in vivo, an enhanced affinity between H3K27M and the allosterically activated state of PRC2, and the displacement of PRC2 from chromatin containing H3K27M. Following these early events upon an introduction of H3K27M into wildtype cells, the steady-state chromatin manifested a global loss of H3K27 methylation but a gain of H3K36 methylaiton, an antagonistic histone modification associated with transcriptional elongation. These observations suggested that H3K36 methylation may function in displacing PRC2 from chromatin and the oncogenic transcription facilitated by H3K36 methylation could be a vulnerability of H3K27M DIPG. Indeed, ectopic expression of H3K36M in H3K27M DIPG cells depleted global H3K36 methylation and exerted an anti-proliferative effect, implicating a potential strategy in targeting the writer and reader proteins for H3K36 methylation against H3K27M DIPG. Citation Format: Jia-Ray Yu, Gary LeRoy, James Stafford, Chul-Hwan Lee, Danny Reinberg. Epigenetic and transcriptional alterations as potential vulnerabilities of diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-104.