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Nature DOI:10.1038/nature16490

Insulator dysfunction and oncogene activation in IDH mutant gliomas.

Publication TypeJournal Article
Year of Publication2016
AuthorsFlavahan, WA, Drier, Y, Liau, BB, Gillespie, SM, Venteicher, AS, Stemmer-Rachamimov, AO, Suvà, ML, Bernstein, BE
Date Published2016 Jan 07
KeywordsBase Sequence, Binding Sites, Cell Cycle Proteins, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Chromatin, Chromosomal Proteins, Non-Histone, CpG Islands, CRISPR-Cas Systems, DNA Methylation, Down-Regulation, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Glioma, Glutarates, Humans, Insulator Elements, Isocitrate Dehydrogenase, Mutation, Oncogenes, Phenotype, Protein Binding, Receptor, Platelet-Derived Growth Factor alpha, Repressor Proteins, Up-Regulation

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.


Alternate JournalNature
PubMed ID26700815
PubMed Central IDPMC4831574
Grant ListP50 CA165962 / CA / NCI NIH HHS / United States
U54 HG006991 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States