Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence Journal Article
| Authors: | Turcan, S.; Makarov, V.; Taranda, J.; Wang, Y.; Fabius, A. W. M.; Wu, W.; Zheng, Y.; El-Amine, N.; Haddock, S.; Nanjangud, G.; LeKaye, H. C.; Brennan, C.; Cross, J.; Huse, J. T.; Kelleher, N. L.; Osten, P.; Thompson, C. B.; Chan, T. A. |
| Article Title: | Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence |
| 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. © 2017 The Author(s). |
| Keywords: | controlled study; unclassified drug; gene mutation; human cell; clinical feature; nonhuman; glioma; mouse; animal tissue; gene expression; animal experiment; animal model; astrocyte; protein; genetic association; genome-wide association study; genetic transcription; cell population; dna methylation; epigenetics; chromatin; myc protein; genomics; doxycycline; tetracycline; cd24 antigen; gene location; nuclear reprogramming; isocitrate dehydrogenase 1; histone methylation; long term exposure; spacer dna; human; female; priority journal; article; max protein; map1lc3a protein; tet1 protein; tricellulin |
| Journal Title: | Nature Genetics |
| Volume: | 50 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-01-01 |
| Start Page: | 62 |
| End Page: | 72 |
| Language: | English |
| DOI: | 10.1038/s41588-017-0001-z |
| PROVIDER: | scopus |
| PMCID: | PMC5769471 |
| PUBMED: | 29180699 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 6 February 2018 -- Source: Scopus |
