Insulator dysfunction and oncogene activation in IDH mutant gliomas

Nature. 2016 Jan 7;529(7584):110-4. doi: 10.1038/nature16490. Epub 2015 Dec 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites
  • CCCTC-Binding Factor
  • CRISPR-Cas Systems / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Cells, Cultured
  • Chromatin / drug effects
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism
  • CpG Islands / genetics
  • DNA Methylation / drug effects
  • DNA Methylation / genetics
  • Down-Regulation / drug effects
  • Enhancer Elements, Genetic / genetics
  • Epigenesis, Genetic / drug effects
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Glioma / drug therapy
  • Glioma / enzymology*
  • Glioma / genetics*
  • Glioma / pathology
  • Glutarates / metabolism
  • Humans
  • Insulator Elements / drug effects
  • Insulator Elements / genetics*
  • Isocitrate Dehydrogenase / chemistry
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism
  • Mutation / genetics*
  • Oncogenes / genetics*
  • Phenotype
  • Protein Binding
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Repressor Proteins / metabolism
  • Up-Regulation

Substances

  • CCCTC-Binding Factor
  • CTCF protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Glutarates
  • Repressor Proteins
  • cohesins
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Receptor, Platelet-Derived Growth Factor alpha

Associated data

  • GEO/GSE70991