Abstract Brain tumors have the worse survival rates of all childhood malignancies, and a better understanding of their biology is needed for therapeutic development. Two especially devastating subtypes of pediatric brain tumors—diffuse midline gliomas, H3K27M-mutant (DMGs) and posterior fossa ependymomas, group A (PFAs) are both characterized by a hallmark of global reduction of histone 3 lysine 27 trimethylation, a mark associated with transcriptional repression. DMGs primarily harbor mutations of histone 3 (H3K27M) that inhibit the function of the H3 methyltransferase enhancer of zeste homolog 2 (EZH2)-containing polycomb repressive complex (PRC2). Most PFAs overexpress EZH inhibitory protein (EZHIP), resulting in a similar effect on PRC2 activity. Intriguingly, a small subset of DMGs found to be lacking H3K27M mutations express EZHIP, and a fraction of histological PFAs lacking EZHIP expression harbor H3K27M mutations. Given the highly similar putative driving alterations and epigenetic features in these two tumor types, we undertook a systematic evaluation of the clinical and molecular features of each tumor class to elucidate additional shared features and potential targetable vulnerabilities. We performed detailed analyses of genomic aberrations, gene expression, and epigenomic landscapes to identify key similarities and differences in tumor biology. From preliminary studies, our findings demonstrate similar H3K27me3 landscapes with convergence of residual tri-methylated loci between PFA and DMG tumors. We additionally found shared recurrent copy number gain of the long arm of chromosome 1 (1q) and identified several 1q genes whose expression correlated with survival differences in cohorts of both tumors. Together, these findings better define the commonalities and differences of these highly aggressive, low-H3K27me3 pediatric brain tumors and will provide a framework for understanding which therapeutic strategies may translate from one tumor to the other. Citation Format: Matthew Pun, Drew Pratt, Sriram Venneti. Identifying shared features of low-H3K27me3 pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6049.