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.

doi:10.64898/2026.06.05.730437

bioRxiv · 10.64898/2026.06.05.730437

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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Abstract

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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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.. 2026-06-09. Single-nucleus multiomics unveils malignant cellular states, regulatory architectures and microenvironmental reorganization across the G-CIMP epigenomic transition in IDH-mutant glioma. https://doi.org/10.64898/2026.06.05.730437

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