Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas1,2. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3,4,5,6,7. TET enzymes catalyse a key step in the removal of DNA methylation8,9. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP)10,11, 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.
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Gene Expression Omnibus
Data generated for this study are available through the Gene Expression Omnibus (GEO) under accession number GSE70991.
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.
This file contains a list of deregulated boundaries and genes. The table lists domains whose boundaries are predicted to be lost based on cross-boundary gene pairs that gain correlation and intra-domain gene pairs that lose correlation. All supporting gene pairs (FDR < 1%) are listed along with their significance. The overall significance of each domain is also shown. Genes that are up-regulated by at least 2-fold in IDH mutant gliomas, relative to the median of the wild-type, are indicated. For each domain, the coordinates of boundaries predicted to be lost are also listed.