IDH Mutations Promote Glioma through Epigenetic Insulator Disruption

Gain-of-function mutations in isocitrate dehydrogenase (IDH) lead to the production of 2-hydroxyglutarate, which disrupts the activity of the TET family DNA demethylases and thus can contribute to CpG island hypermethylation. However, the functional relevance of enhanced CpG methylation in glioma is not well understood. CCCTC-binding factor (CTCF) is a methylation-sensitive insulator protein involved in creating chromatin boundaries. To determine if IDH-dependent hypermethylation altered CTCF binding, Flavahan, Drier, and colleagues performed CTCF chromatin immunoprecipitation sequencing (ChIP-seq) of gliomas, and obtained DNA methylation profiles from The Cancer Genome Atlas. CTCF occupancy was reduced at more sites than it was increased in IDH-mutant gliomas, and the CTCF-deficient sites had higher GC content and increased DNA methylation than IDH–wild-type gliomas. Based on constitutive domain boundaries and RNA-seq data, IDH mutant gliomas had an increased correlation between genes normally insulated from each other by topological domain boundaries. The increased correlation raised the possibility that reduced CTCF binding in IDH-mutant gliomas may disrupt topological domain boundaries. Approximately 200 domain boundaries disrupted by IDH mutation were identified, and genes located adjacent to these boundaries showing increased expression in IDH-mutant gliomas included known glioma oncogenes such as PDGFRA. In IDH-mutant gliomas, PDGFRA expression was correlated with expression of FIP1L1, a housekeeping gene normally located in a distinct domain separated from PDGFRA by a CTCF-bound constitutive boundary. In IDH-mutant gliomas, CTCF occupancy at this boundary was reduced, and the PDGFRA promoter interacted with the FIP1L1 enhancer instead of its cognate enhancer as in IDH–wild-type glioma. Treatment with the DNA methyltransferase inhibitor 5-azacytidine reduced methylation of the CTCF motif, increased CTCF binding, and downregulated PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF boundary element also increased PDGFRA expression, and promoted glioma cell growth. Altogether, these findings demonstrate that IDH mutations can promote glioma growth through disruption of boundary elements and impaired oncogene insulation.

Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 2016;529:110–4.

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