Oncogenic IDH1drives robust loss of histone acetylation and increases chromatin heterogeneity.

in Proceedings of the National Academy of Sciences of the United States of America by Noa Furth, Niv Cohen, Avishay Spitzer, Tomer-Meir Salame, Bareket Dassa, Tevie Mehlman, Alexander Brandis, Arieh Moussaieff, Dinorah Friedmann-Morvinski, Maria G Castro, Jerome Fortin, Mario L Suvà, Itay Tirosh, Ayelet Erez, Guy Ron, Efrat Shema

TLDR

  • The study explores the epigenetic alterations in glioma cells with mutant IDH1 and reveals extensive remodeling of chromatin patterns and deregulation of histone acetylation marks.
  • The findings highlight the complex interplay between chromatin and metabolism dysregulation in glioma and its impact on epigenetic and oncogenic pathways.

Abstract

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 (IDH1/2) 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 (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype. Yet, the complete depiction of the epigenetic alterations in IDHcells 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.

Overview

  • The study focuses on the effect of mutant IDH1 on epigenetic alterations in glioma cells.
  • The study uses an unbiased approach, leveraging CyTOF analysis, to profile the effect of mutant-IDH1 on a broad panel of histone modifications at single-cell resolution.
  • The study aims to understand the complete depiction of the epigenetic alterations in IDH mutant cells and its impact on chromatin patterns, histone modifications, and gene expression.

Comparative Analysis & Findings

  • The study reveals 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.
  • The changes in acetylation are not predominantly driven by 2-HG, and can be rescued by pharmacological inhibition of mutant-IDH1, and reversed by acetate supplementations.

Implications and Future Directions

  • The study highlights the tight interaction between chromatin and metabolism dysregulation in glioma and its impact on epigenetic and oncogenic pathways.
  • Future studies can explore the therapeutic potential of targeting epigenetic and oncogenic pathways affected by mutant-IDH1-driven metabolic rewiring.
  • This study also underscores the need for further research on the causative role of mutant-IDH1 in gliomagenesis and its potential as a therapeutic target.
Read Full Article