IDH mutations in gliomas lead to the production of 2-hydroxyglutarate (2-HG), which disrupts DNA methylation and causes hypermethylation of CTCF binding sites. This reduces CTCF binding, compromising insulation between topological domains and leading to aberrant gene activation. The study shows that IDH mutant gliomas exhibit hypermethylation at CTCF binding sites, which reduces CTCF binding and allows constitutive enhancers to interact with oncogenes like PDGFRA. Treatment with demethylating agents restores CTCF function and down-regulates PDGFRA. Conversely, CRISPR-mediated disruption of CTCF in IDH wildtype gliomas up-regulates 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 human genome is organized into topological domains, and CTCF plays a key role in creating chromatin loops and boundaries that partition these domains. Genomic alterations that remove CTCF-associated boundaries allow aberrant enhancer-gene interactions and alter gene expression. The study used ChIP-seq to map CTCF binding in gliomas and found that IDH mutant gliomas have higher DNA methylation and lower CTCF binding at specific boundaries. This disrupts domain boundaries and gene insulation, leading to altered gene expression. The study also found that IDH mutant gliomas have a higher correlation between genes that cross domain boundaries, suggesting that altered domain topology contributes to oncogene activation. The study highlights the role of CTCF in maintaining chromatin structure and gene regulation, and shows that IDH mutations disrupt this process, leading to oncogene activation and tumor progression. The findings have implications for understanding the epigenetic mechanisms underlying gliomagenesis and may inform the development of targeted therapies for IDH mutant gliomas.IDH mutations in gliomas lead to the production of 2-hydroxyglutarate (2-HG), which disrupts DNA methylation and causes hypermethylation of CTCF binding sites. This reduces CTCF binding, compromising insulation between topological domains and leading to aberrant gene activation. The study shows that IDH mutant gliomas exhibit hypermethylation at CTCF binding sites, which reduces CTCF binding and allows constitutive enhancers to interact with oncogenes like PDGFRA. Treatment with demethylating agents restores CTCF function and down-regulates PDGFRA. Conversely, CRISPR-mediated disruption of CTCF in IDH wildtype gliomas up-regulates 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 human genome is organized into topological domains, and CTCF plays a key role in creating chromatin loops and boundaries that partition these domains. Genomic alterations that remove CTCF-associated boundaries allow aberrant enhancer-gene interactions and alter gene expression. The study used ChIP-seq to map CTCF binding in gliomas and found that IDH mutant gliomas have higher DNA methylation and lower CTCF binding at specific boundaries. This disrupts domain boundaries and gene insulation, leading to altered gene expression. The study also found that IDH mutant gliomas have a higher correlation between genes that cross domain boundaries, suggesting that altered domain topology contributes to oncogene activation. The study highlights the role of CTCF in maintaining chromatin structure and gene regulation, and shows that IDH mutations disrupt this process, leading to oncogene activation and tumor progression. The findings have implications for understanding the epigenetic mechanisms underlying gliomagenesis and may inform the development of targeted therapies for IDH mutant gliomas.