Three-dimensional regulatory hubs support oncogenic programs in glioblastoma Journal Article

   


Authors: Breves, S. L.; Di Giammartino, D. C.; Nicholson, J.; Cirigliano, S.; Mahmood, S. R.; Lee, U. J.; Martinez-Fundichely, A.; Jungverdorben, J.; Singhania, R.; Rajkumar, S.; Kirou, R.; Studer, L.; Khurana, E.; Polyzos, A.; Fine, H. A.; Apostolou, E.
Article Title: Three-dimensional regulatory hubs support oncogenic programs in glioblastoma
Abstract: Dysregulation of enhancer-promoter communication in the three-dimensional (3D) nucleus is increasingly recognized as a potential driver of oncogenic programs. Here, we profiled the 3D enhancer-promoter networks of patient-derived glioblastoma stem cells to identify central regulatory nodes. We focused on hyperconnected 3D hubs and demonstrated that hub-interacting genes exhibit high and coordinated expression at the single-cell level and are associated with oncogenic programs that distinguish glioblastoma from low-grade glioma. Epigenetic silencing of a recurrent hub—with an uncharacterized role in glioblastoma—was sufficient to cause downregulation of hub-connected genes, shifts in transcriptional states, and reduced clonogenicity. Integration of datasets across 16 cancers identified “universal” and cancer-type-specific 3D hubs that enrich for oncogenic programs and factors associated with worse prognosis. Genetic alterations could explain only a small fraction of hub hyperconnectivity and increased activity. Overall, our study provides strong support for the potential central role of 3D regulatory hubs in controlling oncogenic programs and properties. © 2025 Elsevier Inc.
Keywords: protein kinase b; cancer survival; controlled study; human cell; promoter region; genetics; liver cell carcinoma; nonhuman; brain tumor; brain neoplasms; endometrium carcinoma; metabolism; hepatocyte nuclear factor 3alpha; gene expression; epidermal growth factor receptor; animal experiment; animal model; immunoglobulin enhancer binding protein; pathology; cell line, tumor; phosphatidylinositol 3 kinase; adrenal cortex carcinoma; ewing sarcoma; gene expression regulation; oncogene; gene expression regulation, neoplastic; lung adenocarcinoma; neoplastic stem cells; epigenetics; epigenesis, genetic; promoter regions, genetic; glioblastoma; histone h3; myc protein; tumor cell line; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; cancer stem cell; vasculotropin a; gene control; androgen receptor; down regulation; thyroid carcinoma; prostate adenocarcinoma; gene regulatory network; cyclin dependent kinase inhibitor 2a; esophagus cancer; stomach adenocarcinoma; hypoxia inducible factor 1alpha; genetic epigenesis; colon adenocarcinoma; oxidative phosphorylation; cyclin dependent kinase 4; notch1 receptor; tumor necrosis factor; rna sequence; clear cell renal cell carcinoma; enhancer region; enhancer elements, genetic; cyclin dependent kinase 6; gene regulatory networks; housekeeping gene; single cell analysis; single-cell analysis; epithelial mesenchymal transition; principal component analysis; mammalian target of rapamycin complex 1; transcription factor sox9; transcription factor runx2; protein c jun; cancer prognosis; spacer dna; guide rna; humans; human; article; rna sequencing; differential gene expression; squamous cell lung carcinoma; clonogenicity; connectome; single-cell rna-seq; single cell rna seq; chromatin immunoprecipitation sequencing; 3d chromatin organization; transitional cell carcinoma of the bladder; structural variants; crispri; hichip; enhancer hubs; enhancer-promoter interactions; oncogenic program; regulatory hubs; pdcd10 gene; wdr49 gene; zbbx gene
Journal Title: Molecular Cell
Volume: 85
Issue: 7
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2025-04-03
Start Page: 1330
End Page: 1348.e6
Language: English
DOI: 10.1016/j.molcel.2025.03.007
PUBMED: 40147440
PROVIDER: scopus
PMCID: PMC12009607
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-105001352407&doi=10.1016%2fj.molcel.2025.03.007&partnerID=40&md5=5527ea75797ff358aa9750be9cca5ed7
Notes: Article -- Source: Scopus
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MSK Authors
  1. Lorenz Studer
    222 Studer
  2. Johannes Christopher Jungverdorben
    8 Jungverdorben
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