Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Flavahan, WA, Drier, Y, Liau, BB, Gillespie, SM, Venteicher, AS, Stemmer-Rachamimov, AO, Suvà, ML, Bernstein, BE |
Journal | Nature |
Volume | 529 |
Issue | 7584 |
Pages | 110-4 |
Date Published | 2016 Jan 07 |
ISSN | 1476-4687 |
Keywords | Base 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 |
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. |
URL | http://dx.doi.org/10.1038/nature16490 |
DOI | 10.1038/nature16490 |
Pubmed | |
Alternate Journal | Nature |
PubMed ID | 26700815 |
PubMed Central ID | PMC4831574 |
Grant List | P50 CA165962 / CA / NCI NIH HHS / United States U54 HG006991 / HG / NHGRI NIH HHS / United States / / Howard Hughes Medical Institute / United States |