Histone 3 centered chromatin dynamics in IDH mutant glioma as diagnostic biomarker and mediator of malignant transition

• Applicant: Dr. Katharina Weber
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549754856

Isocitrate dehydrogenase (IDH) mutant gliomas represent a subtype of primary brain tumors occurring predominantly in early- to mid-adulthood and currently lacking curative treatment options. Treatment regimens vary according to the tumors’ biological aggressiveness. IDH mutant glioma is classified in up to three malignancy grades commonly increasing upon tumor recurrence indicating malignant transition. The timing of treatment initiation is crucial to stem tumor growth especially of gliomas prone to malignant transition while mitigating neurotoxicity from aggressive radio-chemotherapy. However, reliable biomarkers to delineate malignant transition remain largely elusive. Histone 3, a fundamental constituent of chromatin, undergoes multiple posttranslational modifications (PTMs), contributing to the regulation of gene expression. Variations in histone 3 modification patterns distinguish subtypes of IDH mutant gliomas, with oligodendrogliomas and astrocytomas in part showing a nuclear lack of trimethylation at histone 3 lysine 27. Furthermore, the incorporation of replication-dependent histone 3 variants in mitotically active cells contrasts with the accumulation of replication-independent variants in non-proliferative, postmitotic cells. Yet the type of histone 3 variant influences the nature of possible PTMs, and this interplay remains unexplored in glioma so far. This study aims at investigating the hypothesis that increasing malignancy grades of IDH-mutant gliomas correlate with alterations of the balance of histone 3 variants and their PTMs in favor of the replication-dependent histone 3 variant trimethylated at lysine 27. Epigenetic methodologies will be employed to analyze DNA and chromatin-associated proteins in human IDH-mutant gliomas and in assimilated mouse neuronal stem cell models, which enable to study separate and mutual effects of the most common glioma mutations (Idh1, Trp53, Atrx, Cic) on chromatin. We will both assess quantitative and qualitative, gene-associated changes in nucleosomal occupancy of histone 3 variants and their PTMs alongside malignancy grades with potential impact on 3D nucleosomal organization. The analyses aim at evaluating the potential biomarker utility of histone 3 centered chromatin dynamics to delineate tumors with proliferative activity, imminent of malignant transition and/or their role as mediators of malignant progression. Having defined the correlative histone 3-PTMs signatures of the malignancy spectrum of glioma, we will investigate whether they can be modified in favor of lower-grade glioma patterns by use of IDH-mutation inhibitors.

• DFG Programme: Research Grants