Three-dimensional regulatory hubs support oncogenic programs in glioblastoma.

in Molecular cell by Sarah L Breves, Dafne Campigli Di Giammartino, James Nicholson, Stefano Cirigliano, Syed Raza Mahmood, Uk Jin Lee, Alexander Martinez-Fundichely, Johannes Jungverdorben, Richa Singhania, Sandy Rajkumar, Raphael Kirou, Lorenz Studer, Ekta Khurana, Alexander Polyzos, Howard A Fine, Effie Apostolou

TLDR

  • The study identifies 3D regulatory hubs as central controllers of oncogenic programs in glioblastoma.
  • These hubs are hyperconnected and play a key role in controlling gene expression and cancer growth.
  • Further research is needed to understand the functional significance of 3D hubs and to identify therapeutic targets.

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.

Overview

  • The study profiles the 3D enhancer-promoter networks of patient-derived glioblastoma stem cells to identify central regulatory nodes.
  • The researchers focused on hyperconnected 3D hubs and demonstrated that hub-interacting genes exhibit high and coordinated expression at the single-cell level.
  • The study aims to understand the potential central role of 3D regulatory hubs in controlling oncogenic programs and properties.

Comparative Analysis & Findings

  • Hub-interacting genes exhibit high and coordinated expression at the single-cell level.
  • Epigenetic silencing of a recurrent hub 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.

Implications and Future Directions

  • The study suggests that 3D regulatory hubs play a central role in controlling oncogenic programs and properties in glioblastoma.
  • Further studies are needed to investigate the functional significance of 3D hubs in various cancers and to identify therapeutic targets.
  • The development of methods to target and modulate 3D hubs could lead to the identification of novel therapies for cancer treatment.
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