Insulator dysfunction and oncogene activation in IDH mutant gliomas

Article

关键词: INTEGRATED GENOMIC ANALYSIS;    METHYLATION;    EXPRESSION;    2-HYDROXYGLUTARATE;    DEMETHYLATION;    ARCHITECTURE;    MAINTENANCE;    PRINCIPLES;    LANDSCAPE;    PHENOTYPE;   

DOI  :  10.1038/nature16490

来源: SCIE

【 摘 要 】

Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas(1,2). Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases(3-7). TET enzymes catalyse a key step in the removal of DNA methylation(8,9). IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP)(10,11), 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.

【 授权许可】

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