@article {625891,
	title = {Insulator dysfunction and oncogene activation in IDH mutant gliomas.},
	journal = {Nature},
	volume = {529},
	number = {7584},
	year = {2016},
	month = {2016 Jan 7},
	pages = {110-4},
	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{\textquoteright}-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.},
	issn = {1476-4687},
	doi = {10.1038/nature16490},
	author = {Flavahan, William A and Drier, Yotam and Liau, Brian B and Gillespie, Shawn M and Venteicher, Andrew S and Stemmer-Rachamimov, Anat O and Suv{\`a}, Mario L and Bernstein, Bradley E}
}
