{"doi":"10.52843/cassyni.mpfjn0","title":"Modeling epigenetic lesions that cause gliomas","abstract":"Diffuse gliomas are the most common malignant primary brain tumors and remain incurable despite aggressive multimodal therapies. Understanding the mechanisms by which gliomas arise is a critical step towards improved therapies. Missense mutations in the metabolic enzyme Isocitrate Dehydrogenase 1 (IDH1) drive a subtype of diffuse gliomas with genome-wide DNA hypermethylation, termed the G-CIMP hypermethylator profile. This profile is caused by mutant IDH1 (IDH1mut) enzyme, which produces 2-hydroxyglutarate (2-HG), an oncometabolite inhibitor of the ten-eleven translocation (TET) demethylases. DNA hypermethylation may promote gliomagenesis by silencing tumor suppressor genes or, alternatively, by activating proto-oncogenes through disruption of CCCTC-binding factor (CTCF) insulators. CTCF insulator sites define the three-dimensional shape of the genome by dictating the boundaries of topologically associating domains (TADs). Enhancers and promoters can interact when located in the same TAD but are restricted from interacting across different TADs. In IDH1mut gliomas, CpG dinucleotides around CTCF binding sites are frequently methylated, effectively compromising CTCF binding and thus TAD organization. Importantly, the effects of TAD reorganization on gene expression are contingent on enhancers, which are cell-type specific. To determine the epigenetic changes that fuel gliomagenesis, we employed a multi-omic approach on clinical IDH1mut glioma samples, leveraging methylation, transcription factor DNA binding, and gene expression analyses. We found a CTCF insulator near the Platelet-derived Growth Factor Receptor A (PDGFRA) proto-oncogene that is recurrently disrupted by methylation. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cyclin-dependent Kinase Inhibitor 2A (Cdkn2a) tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Our study demonstrates the capacity of recurrent epigenetic lesions to drive gliomagenesis.","journal":null,"year":2024,"id":489818,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":95867,"name":"Gilbert J. Rahme","orcid":"0000-0001-6060-1279","position":0,"is_corresponding":true}],"reference_count":1,"raw_metadata":null,"created_at":"2026-07-19T02:08:28.548530Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}