Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence

Sevin Turcan*, Vladimir Makarov, Julian Taranda, Yuxiang Wang, Armida W.M. Fabius, Wei Wu, Yupeng Zheng, Nour El-Amine, Sara Haddock, Gouri Nanjangud, H. Carl LeKaye, Cameron Brennan, Justin Cross, Jason T. Huse, Neil L. Kelleher, Pavel Osten, Craig B. Thompson, Timothy A. Chan

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Mutations in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2) drive the development of gliomas and other human malignancies. Mutant IDH1 induces epigenetic changes that promote tumorigenesis, but the scale and reversibility of these changes are unknown. Here, using human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant-IDH1-induced epigenomic reprogramming. We characterize the reversibility of the alterations in DNA methylation, the histone landscape, and transcriptional reprogramming that occur following IDH1 mutation. We discover genome-wide coordinate changes in the localization and intensity of multiple histone marks and chromatin states. Mutant IDH1 establishes a CD24+ population with a proliferative advantage and stem-like transcriptional features. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented high-resolution molecular portraits of mutant-IDH1-dependent epigenomic reprogramming. These findings have substantial implications for understanding of mutant IDH function and for optimizing therapeutic approaches to targeting IDH-mutant tumors.

Original languageEnglish
Pages (from-to)62-72
Number of pages11
JournalNature Genetics
Volume50
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

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