F.2 Comprehensively mapping transcriptionally relevant histone modifications in aggressive meningioma leads to novel biologic insights and therapeutic vulnerabilities

Abstract

Background: We recently identified four molecular subgroups of meningioma with distinct biology and outcomes. While two (MG3/MG4) are associated with poor outcome, they display divergent transcriptional profiles (enriched in metabolic and cell cycling pathways, respectively) and therapeutic vulnerabilities (MG3 has no clear treatment target). We sought to understand drivers of these key differences at a chromatin level. Methods: We profiled MG3/MG4 meningiomas for common histone marks H3K27me3, H3K27Ac, H3K4me1, H3K4me3, H3K9me3, and H3K36me3. Multiple computational approaches were used to compare MG3 and MG4 tumours including superenhancer ranking, differential binding analysis, and unsupervised clustering. Results: Our cohort includes 11-20 meningiomas per histone mark. Clustering revealed striking separation of subgroups based on multiple histone marks, particularly H3K36me3. FOXC1, a known driver of the epithelial to mesenchymal transition, was identified as a recurrent superenhancer in both groups, whereas MG3-specific superenhancers mapped to immune regulatory networks. Integrated differential binding analysis confirmed an immune-rich microenvironment in MG3 tumours driven by multiple histone marks, suggesting a role for targeting novel immune checkpoint genes CD84 and CD48. Conclusions: This study is the first to apply integrated analysis of multiple histone modifications to aggressive meningioma. We further characterize MG3 tumours by identifying an epigenetically-driven immune phenotype and propose novel treatment targets.