The study investigates the role of insulator dysfunction and oncogene activation in IDH mutant gliomas. IDH mutations lead to the production of 2-hydroxyglutarate (2-HG), which interferes with iron-dependent hydroxylases, including TET enzymes that remove DNA methylation. This results in a CpG island methylator phenotype (G-CIMP) in IDH mutant gliomas. The authors found that these tumors exhibit hypermethylation at CTCF binding sites, leading to reduced CTCF binding and compromised insulation between topological domains. This disruption allows aberrant gene activation, particularly of the PDGFRA oncogene, which is a prominent target in gliomas. Treatment with demethylating agents partially restores insulator function and down-regulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in wildtype gliomas upregulates PDGFRA and increases proliferation. The study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.The study investigates the role of insulator dysfunction and oncogene activation in IDH mutant gliomas. IDH mutations lead to the production of 2-hydroxyglutarate (2-HG), which interferes with iron-dependent hydroxylases, including TET enzymes that remove DNA methylation. This results in a CpG island methylator phenotype (G-CIMP) in IDH mutant gliomas. The authors found that these tumors exhibit hypermethylation at CTCF binding sites, leading to reduced CTCF binding and compromised insulation between topological domains. This disruption allows aberrant gene activation, particularly of the PDGFRA oncogene, which is a prominent target in gliomas. Treatment with demethylating agents partially restores insulator function and down-regulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in wildtype gliomas upregulates PDGFRA and increases proliferation. The study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.