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. 2025 Apr 3;85(7):1330-1348.e6.
doi: 10.1016/j.molcel.2025.03.007. Epub 2025 Mar 26.

Three-dimensional regulatory hubs support oncogenic programs in glioblastoma

Sarah L Breves  1 , Dafne Campigli Di Giammartino  2 , James Nicholson  3 , Stefano Cirigliano  3 , Syed Raza Mahmood  2 , Uk Jin Lee  2 , Alexander Martinez-Fundichely  4 , Johannes Jungverdorben  5 , Richa Singhania  3 , Sandy Rajkumar  2 , Raphael Kirou  2 , Lorenz Studer  5 , Ekta Khurana  4 , Alexander Polyzos  2 , Howard A Fine  6 , Effie Apostolou  7
Affiliations

Three-dimensional regulatory hubs support oncogenic programs in glioblastoma

Sarah L Breves et al. Mol Cell. .

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.

Keywords: 3D chromatin organization; CRISPRi; HiChIP; clonogenicity; enhancer hubs; enhancer-promoter interactions; glioblastoma; oncogenic program; regulatory hubs; single-cell RNA-seq; structural variants.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

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