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Enhancer-promoter hubs organize transcriptional networks promoting oncogenesis and drug resistance

Author

Listed:
  • Brent S. Perlman

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Noah Burget

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Yeqiao Zhou

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Gregory W. Schwartz

    (University Health Network
    University of Toronto)

  • Jelena Petrovic

    (Genentech)

  • Zora Modrusan

    (Genentech)

  • Robert B. Faryabi

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

Abstract

Recent advances in high-resolution mapping of spatial interactions among regulatory elements support the existence of complex topological assemblies of enhancers and promoters known as enhancer-promoter hubs or cliques. Yet, organization principles of these multi-interacting enhancer-promoter hubs and their potential role in regulating gene expression in cancer remain unclear. Here, we systematically identify enhancer-promoter hubs in breast cancer, lymphoma, and leukemia. We find that highly interacting enhancer-promoter hubs form at key oncogenes and lineage-associated transcription factors potentially promoting oncogenesis of these diverse cancer types. Genomic and optical mapping of interactions among enhancer and promoter elements further show that topological alterations in hubs coincide with transcriptional changes underlying acquired resistance to targeted therapy in T cell leukemia and B cell lymphoma. Together, our findings suggest that enhancer-promoter hubs are dynamic and heterogeneous topological assemblies with the potential to control gene expression circuits promoting oncogenesis and drug resistance.

Suggested Citation

  • Brent S. Perlman & Noah Burget & Yeqiao Zhou & Gregory W. Schwartz & Jelena Petrovic & Zora Modrusan & Robert B. Faryabi, 2024. "Enhancer-promoter hubs organize transcriptional networks promoting oncogenesis and drug resistance," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52375-6
    DOI: 10.1038/s41467-024-52375-6
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