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

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 Harmancı, Victoria E. Clark, Daniel Duran, Anita Huttner, Timuçin Avşar, Yasar Bayri, Johannes Schramm, Julien Boetto, Matthieu Peyre, Maximilien Riche, Roland Goldbrunner, Nduka Amankulor, Angeliki Louvi, Kaya Bilgüvar, M. Necmettin Pamir, Koray Özduman, Türker Kilic, James R. Knight, Matthias Simon, Craig Horbinski, Michel Kalamarides, Marco Timmer, Amy B. Heimberger, Ketu Mishra-Gorur, Jennifer Moliterno, Katsuhito Yasuno () and Murat Günel ()
Additional contact information
Mark W. Youngblood: Yale School of Medicine
Zeynep Erson-Omay: Yale School of Medicine
Chang Li: Yale School of Medicine
Hinda Najem: Northwestern University
Süleyman Coșkun: Yale School of Medicine
Evgeniya Tyrtova: Yale School of Medicine
Julio D. Montejo: Yale School of Medicine
Danielle F. Miyagishima: Yale School of Medicine
Tanyeri Barak: Yale School of Medicine
Sayoko Nishimura: Yale School of Medicine
Akdes Serin Harmancı: Yale School of Medicine
Victoria E. Clark: Yale School of Medicine
Daniel Duran: Yale School of Medicine
Anita Huttner: 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
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
Kaya Bilgüvar: Yale School of Medicine
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
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
Jennifer Moliterno: Yale School of Medicine
Katsuhito Yasuno: Yale School of Medicine
Murat Günel: Yale School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41926-y

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