Oncogenic IDH1mut drives robust loss of histone acetylation and increases chromatin heterogeneity

• 成果类型: Article
• 署名作者: Furth, Noa; Cohen, Niv; Spitzer, Avishay; Salame, Tomer- Meir; Dassa, Bareket; Mehlman, Tevie; Brandis, Alexander; Moussaieff, Arieh; Friedmann-Morvinski, Dinorah; Castro, Maria G.; Fortin, Jerome; Suva, Mario L.; Tirosh, Itay; Erez, Ayelet; Ron, Guy; Shema, Efrat
• 署名单位: Weizmann Institute of Science; Weizmann Institute of Science; Tel Aviv University; Sackler Faculty of Medicine; Tel Aviv Sourasky Medical Center; Tel Aviv University; Weizmann Institute of Science; Weizmann Institute of Science; Weizmann Institute of Science; Hebrew University of Jerusalem; Tel Aviv University; University of Michigan System; University of Michigan; McGill University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); Hebrew University of Jerusalem
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14345
• DOI: 10.1073/pnas.2403862122
• 发表日期: 2025-01-07
• 关键词: isocitrate dehydrogenase 1; 2 mutations; idh1; cancer; metabolism; activation; enhancers

摘要

Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2mut) enzymes are predominantly found in low- grade gliomas and secondary high- grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain- of- function activity that favors the conversion of a- ketoglutarate (ox- KG) to the oncometabolite 2- hydroxyglutarate (2- HG), resulting in an aberrant hypermethylation phenotype. Yet, the complete depiction of the epigenetic alterations in IDHmut cells has not been thoroughly explored. Here, we applied an unbiased approach, leveraging epigenetic- focused cytometry by time- of- flight (CyTOF) analysis, to systematically profile the effect of mutant-IDH1 expression on a broad panel of histone modifications at single- cell resolution. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH1, with the most prominent being deregulation of histone acetylation marks. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Notably, the changes in acetylation are not predominantly driven by 2- HG, can be rescued by pharmacological inhibition of mutant-IDH1, and reversed by acetate supplementations. Furthermore, cells expressing mutant-IDH1 show higher epigenetic and transcriptional heterogeneity and upregulation of oncogenes such as KRAS and MYC, highlighting its tumorigenic potential. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma and highlights epigenetic and oncogenic pathways affected by mutant-IDH1- driven metabolic rewiring.