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Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas

Author

Listed:
  • Mark W. Youngblood

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine
    Northwestern University)

  • Zeynep Erson-Omay

    (Yale School of Medicine
    Yale School of Medicine)

  • Chang Li

    (Yale School of Medicine
    Yale School of Medicine
    Sun Yat-sen University Cancer Center)

  • Hinda Najem

    (Northwestern University)

  • Süleyman Coșkun

    (Yale School of Medicine
    Yale School of Medicine
    Middle East Technical University)

  • Evgeniya Tyrtova

    (Yale School of Medicine
    Yale School of Medicine
    University of Washington)

  • Julio D. Montejo

    (Yale School of Medicine
    Yale School of Medicine
    Dartmouth-Hitchcock Medical Center)

  • Danielle F. Miyagishima

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine)

  • Tanyeri Barak

    (Yale School of Medicine
    Yale School of Medicine)

  • Sayoko Nishimura

    (Yale School of Medicine
    Yale School of Medicine)

  • Akdes Serin Harmancı

    (Yale School of Medicine
    Yale School of Medicine
    Baylor College of Medicine)

  • Victoria E. Clark

    (Yale School of Medicine
    Yale School of Medicine
    Massachusetts General Hospital and Harvard Medical School)

  • Daniel Duran

    (Yale School of Medicine
    Yale School of Medicine
    University of Mississippi Medical Center)

  • Anita Huttner

    (Yale School of Medicine
    Yale School of Medicine)

  • Timuçin Avşar

    (Bahcesehir University, School of Medicine)

  • Yasar Bayri

    (Marmara University School of Medicine)

  • Johannes Schramm

    (University of Bonn Medical School)

  • Julien Boetto

    (Hopital Pitie-Salpetriere, AP-HP & Sorbonne Université
    Montpellier University Medical Center)

  • Matthieu Peyre

    (Hopital Pitie-Salpetriere, AP-HP & Sorbonne Université)

  • Maximilien Riche

    (Hopital Pitie-Salpetriere, AP-HP & Sorbonne Université)

  • Roland Goldbrunner

    (University Hospital of Cologne)

  • Nduka Amankulor

    (University of Pennsylvania)

  • Angeliki Louvi

    (Yale School of Medicine
    Yale School of Medicine)

  • Kaya Bilgüvar

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine
    Yale University West Campus)

  • M. Necmettin Pamir

    (Acibadem Mehmet Ali Aydınlar University, School of Medicine)

  • Koray Özduman

    (Acibadem Mehmet Ali Aydınlar University, School of Medicine)

  • Türker Kilic

    (Bahcesehir University, School of Medicine)

  • James R. Knight

    (Yale University West Campus)

  • Matthias Simon

    (University of Bonn Medical School
    University of Bielefeld Medical Center OWL)

  • Craig Horbinski

    (Northwestern University)

  • Michel Kalamarides

    (Hopital Pitie-Salpetriere, AP-HP & Sorbonne Université)

  • Marco Timmer

    (University Hospital of Cologne)

  • Amy B. Heimberger

    (Northwestern University)

  • Ketu Mishra-Gorur

    (Yale School of Medicine
    Yale School of Medicine)

  • Jennifer Moliterno

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine)

  • Katsuhito Yasuno

    (Yale School of Medicine
    Yale School of Medicine)

  • Murat Günel

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine
    University of Pennsylvania)

Abstract

Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway in neoplasia.

Suggested Citation

  • Mark W. Youngblood & Zeynep Erson-Omay & Chang Li & Hinda Najem & Süleyman Coșkun & Evgeniya Tyrtova & Julio D. Montejo & Danielle F. Miyagishima & Tanyeri Barak & Sayoko Nishimura & Akdes Serin Harma, 2023. "Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41926-y
    DOI: 10.1038/s41467-023-41926-y
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    References listed on IDEAS

    as
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