Insulator dysfunction and oncogene activation in IDH mutant gliomas

By William A. Flavahan, Y. Drier, Brian B Liau, Shawn M. Gillespie, Andrew S. Venteicher, A. Stemmer-Rachamimov, M. Suvà, Bradley E. Bernstein. Nature, 2015

1,173 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/749f7a7a14c60dad4fd2f91895fe8ba804d72f81

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Citations in the corpus

Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition (2017, background): “We also examined whether loops 8 and TADs 15,16 , prominent functional features of chromatin organization 17–19 , are present in individual cells.”
Cohesin loss eliminates all loop domains (2017, background): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript domains (Flavahan et al., 2016; Lupiáñez et al., 2015).”
Epigenetic plasticity and the hallmarks of cancer (2017, background): “Specifically, the expression of proximal genes separated byaCTCF insulator ismorehighly correlated in IDH mutant tumors than in normal cell types (48, 49).”
Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization (2017, neutral): “This highlights the crucial role of boundaries in mediating the physical insulation of neighboring chromosome domains, with important implications for disease-causing chromosomal rearrangements in humans (Flavahan et al., 2016; Franke et al., 2016; Hnisz et al., 2016).”
Residual Convolutional Neural Network for Determination of IDH Status in Low- and High-grade Gliomas from MR Imaging (2017, background): “When IDH is mutated, the conversion of isocitrate is instead driven to 2-hydroxyglutarate, which inhibits downstream histone demethylases (9).”
Transcriptional Addiction in Cancer (2017, positive): “In glioma cells that harbor mutations in the IDH1 gene, hypermethylation of insulated neighborhood anchor sites occurs, which leads to loss of CTCF binding at those anchors and activation of oncogenes that were previously silent in the intact neighborhoods (Flavahan et al., 2016).”
Ever-changing landscapes: transcriptional enhancers in development and evolution (2016, background): “Formation of TAD Boundaries and CTCF-Mediated Loops Since TAD boundaries appear to restrict both enhancer function (Dowen et al., 2014; Flavahan et al., 2016; Guo et al., 2015; Lupiáñez et al., 2015) and spreading of chromatin marks”
Regulation of disease-associated gene expression in the 3D genome (2016, positive): “Indeed, reduced CTCF binding was observed at many genomic positions, TAD borders were weakened or disrupted, and a prominent glioma onco gene was brought under the control of an enhancer in a neighbouring TAD 144 .”