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.

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Acknowledgements

We thank the members of the Chan and Thompson laboratories for helpful discussions. This work was supported in part by the US National Institutes of Health (NIH; R01 CA177828) (T.A.C. and C.B.T.), the MSKCC Brain Tumor Center (S.T. and T.A.C.), the Sontag Foundation (T.A.C.), the PaineWebber Chair Endowment (T.A.C.), NIH T32 grant 5T32CA160001 (S.T.), the MSKCC Society (T.A.C.), the NIH (R01 MH096946) (P.O.), and NIH Cancer Center Support Grant P30CA008748 (G.N.). This research was carried out in collaboration with the National Resource for Translational and Developmental Proteomics under grant P41 GM108569 (N.L.K.) from the National Institute of General Medical Sciences, NIH.

Author information

Author notes

    • Sevin Turcan

    Present address: Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany

    • Armida W. M. Fabius

    Present address: Department of Ophthalmology, VU Medical Center, Amsterdam, The Netherlands

Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Sevin Turcan
    • , Vladimir Makarov
    • , Yuxiang Wang
    • , Armida W. M. Fabius
    • , Wei Wu
    • , Sara Haddock
    • , Jason T. Huse
    •  & Timothy A. Chan
  2. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    • Julian Taranda
    • , Nour El-Amine
    •  & Pavel Osten
  3. Sanofi Genzyme, Waltham, MA, USA

    • Yupeng Zheng
  4. Weill Cornell School of Medicine, New York, NY, USA

    • Sara Haddock
    •  & Timothy A. Chan
  5. Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Gouri Nanjangud
  6. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • H. Carl LeKaye
  7. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Cameron Brennan
  8. Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Justin Cross
  9. Department of Chemistry, Northwestern University, Evanston, IL, USA

    • Neil L. Kelleher
  10. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Craig B. Thompson
  11. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Timothy A. Chan

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Contributions

S.T. and T.A.C. conceived of the study. S.T., V.M., J.T., Y.W., A.W.M.F., W.W., Y.Z., N.E.-A., S.H., G.N., H.C.L., C.B., J.C., and J.T.H. performed the experiments. S.T., V.M., J.T., Y.W., A.W.M.F., Y.Z., N.E.-A., S.H., G.N., H.C.L., C.B., J.C., J.T.H., N.L.K., P.O., and T.A.C. analyzed the results. T.A.C. and C.B.T. supervised the project. All authors contributed to the writing or editing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sevin Turcan or Timothy A. Chan.

Integrated supplementary information

Supplementary information

  1. Combined Supplementary Information

    Supplementary Figures 1–11

  2. Life Sciences Reporting Summary

  3. Supplementary Video 1

    Whole-brain surface reconstruction (Dox) from 280 brain sections imaged with STP tomography with 20% resolution of raw data

  4. Supplementary Video 2

    Whole-brain surface and 3D tumor reconstruction (Dox+) from 280 brain sections imaged with STP tomography with 20% resolution of raw data

  5. Supplementary Video 3

    Whole-brain surface and 3D tumor reconstruction (Doxoff) from 280 brain sections imaged with STP tomography with 20% resolution of raw data

  6. Supplementary Table 1

    Up- and downregulated gene expression clusters following doxycycline withdrawal

  7. Supplementary Table 2

    Differentially expressed genes in IDH1 R132H Dox+ inducible IHAs sorted by CD24 expression (CD24+ versus CD24)

  8. Supplementary Table 3

    Hyper- and hypomethylated clusters following doxycycline withdrawal

  9. Supplementary Table 4

    H3K4me3 enrichment at the transcription start sites (TSSs) of Dox and Dox+ IDH1 R132H IHAs

  10. Supplementary Table 5

    FPKM values of RNA-seq data from inducible astrocytes and tumorspheres

  11. Supplementary Table 6

    Top 11,445 significantly H3K4me3-enriched regions in Dox+ IHAs

  12. Supplementary Table 7

    Primers used for qPCR analysis of selected ERVs