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

Turcan, Sevin, Makarov, Vladimir, Taranda, Julian, Wang, Yuxiang, Fabius, Armida W. M., Wu, Wei, Zheng, Yupeng, El-Amine, Nour, Haddock, Sara, Nanjangud, Gouri, LeKaye, H. Carl, Brennan, Cameron, Cross, Justin, Huse, Jason T., Kelleher, Neil L., Osten, Pavel, Thompson, Craig B., Chan, Timothy A. (January 2018) Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nature Genetics, 50 (1). pp. 62-72. ISSN 1546-1718

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URL: https://www.ncbi.nlm.nih.gov/pubmed/29180699

DOI: 10.1038/s41588-017-0001-z

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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromatin remodeling bioinformatics > genomics and proteomics > genetics & nucleic acid processing > epigenetics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > epigenetics
CSHL Authors:	Taranda, Julian Osten, Pavel El-Amine, Nour
Communities:	CSHL Cancer Center Shared Resources > Microscopy Service CSHL labs > Osten lab
Depositing User:	Matt Covey
Date:	January 2018
Date Deposited:	29 Nov 2017 15:23
Last Modified:	25 Oct 2018 16:14
PMCID:	PMC5769471
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/35673

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