Single-nucleus multiomics unveils malignant cellular states, regulatory architectures and microenvironmental reorganization across the G-CIMP epigenomic transition in IDH-mutant glioma
Herrgott, G.; Garofano, L.; Silva Morosini, N.; Done, B.; Powell, C. L.; deCarvalho, A.; Hasselbach, L.; Transou, A.; Lee, I.; Walbert, T.; Snyder, J.; Lasorella, A.; Castro, A. V.; Iavarone, A.; Noushmehr, H.
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IDH-mutant gliomas stratified by glioma CpG island methylator phenotype (G-CIMP) into High (GCH) and Low (GCL) exhibit markedly divergent clinical outcomes, yet cellular and regulatory determinants of this distinction remain incompletely defined. Integrating single-nucleus RNA-and ATAC-sequencing across 18 tumor specimens from 10 patients, we resolved six malignant cellular states whose differential enrichment across G-CIMP strata delineates the GCL epigenomic transition. GCL tumors were enriched for independently prognostic Mesenchymal and Mitotic Proliferative states, driven by convergent E2F, MYC, MEF2, and NFI-family regulatory networks confirmed across chromatin, histone, and transcriptomic modalities. Pseudotime trajectory inference revealed a multifurcating developmental model from an Astrocytic-like origin, with GCL tumors gaining preferential access to proliferative and mesenchymal endpoints. A reorganized immune microenvironment and candidate therapeutic axes including CDK4/6-E2F, MYC/BET, KIF11, and NOTCH, potentially combinable with vorasidenib as an epigenomic backbone provide a translationally actionable framework for intercepting GCL progression in IDH-mutant glioma.
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