Insulator dysfunction and oncogene activation in IDH mutant gliomas

William A. Flavahan, Yotam Drier, Brian B. Liau, Shawn M. Gillespie, Andrew S. Venteicher, Anat O. Stemmer-Rachamimov, Mario L. Suvà, Bradley E. Bernstein

Research output: Contribution to journalArticlepeer-review

501 Scopus citations

Abstract

Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.

Original languageEnglish (US)
Pages (from-to)110-114
Number of pages5
JournalNature
Volume529
Issue number7584
DOIs
StatePublished - Jan 7 2016
Externally publishedYes

Bibliographical note

Funding Information:
We thank J. Kim, the MGH Neuro Oncology Tissue Repository, and the MGH Pathology Flow Cytometry Core for assistance with clinical samples and analysis, and E. Lander and W. Kaelin for discussions. W.A.F. is supported by a basic research fellowship from the American Brain Tumor Association. B.B.L. is supported by a Jane Coffin Childs fellowship. B.E.B. is an American Cancer Society Research Professor. This research was supported by funds from Howard Hughes Medical Institute, the National Brain Tumor Society and the National Human Genome Research Institute.

Funding Information:
Acknowledgements We thank J. Kim, the MGH Neuro Oncology Tissue Repository, and the MGH Pathology Flow Cytometry Core for assistance with clinical samples and analysis, and E. Lander and W. Kaelin for discussions. W.A.F. is supported by a basic research fellowship from the American Brain Tumor Association. B.B.L. is supported by a Jane Coffin Childs fellowship. B.E.B. is an American Cancer Society Research Professor. This research was supported by funds from Howard Hughes Medical Institute, the National Brain Tumor Society and the National Human Genome Research Institute.

Publisher Copyright:
© 2016 Macmillan Publishers Limited. All rights reserved.

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