High-dimensional analysis reveals increased chromatin heterogeneity and reduced histone acetylation driven by mutant-IDH1 [MARS-seq]

Malignant gliomas are heterogeneous tumors arising in the central nervous system (CNS) driven by epigenetic and metabolic aberrations. Mutations in Isocitrate DeHydrogenase (IDH1/2) enzymes, highly frequent in adult gliomas, confer a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-KG-dependent enzymes. These include DNA and histone lysine demethylases, resulting in an aberrant hypermethylation phenotype in mutant-IDH-expressing cells. Leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, we profiled the effect of mutant-IDH1 expression on a broad panel of histone modifications. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH, with a global reduction in histone acetylation being the most prominent alteration. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Furthermore, cells expressing mutant-IDH1 showed higher epigenetic heterogeneity, which may support the tumorigenic potential of these cells. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma, highlighting novel epigenetic pathways affected by mutant-IDH1-driven metabolic rewiring.