Will Flavahan, Yotam Drier, et al. demonstrate that hypermethylation-induced loss of genomic insulator function causes the development of oncogenic genome topology configurations in IDH1-mutant glioma. This topological restructuring allows a constitutive housekeeping enhancer to interact with and drive the potent glioma oncogene PDGFRA.
-The hypermethylator phenotype observed in IDH1-mutant glioma extends to CpGs present in the binding sites of the methylation-sensitive insulator protein, CTCF, leading to loss of key insulators in these cells.
-Loss of an insulator protecting PDGFRA results in oncogene activation and tumor progression.
-Treatment of IDH1 mutant cells with the DNMT inhibitor 5-azacytidine allowed restoration of insulator function and silencing of PDGFRA.
-CRISPR deletion of insulators in IDH1 wild type glioma cells activated PDGFRA expression and increased cellular proliferation in a PDGFRA-dependent manner.
Insulator dysfunction and oncogene activation in IDH mutant gliomas.
Flavahan WA*, Drier Y*, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suvà ML, Bernstein BE. Nature. 2016 Jan 7;529(7584):110-4. doi: 10.1038/nature16490.