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; Murat Günel

doi:10.1038/s41467-023-41926-y

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

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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, …

Nature communications, Vol.14(1), pp.6279-16

07/10/2023

DOI: https://doi.org/10.1038/s41467-023-41926-y

PMID: 37805627

Résumé

Hedgehog Proteins - genetics

Hedgehog Proteins - metabolism

Humans

Ligands

Meningeal Neoplasms - genetics

Meningioma - genetics

Signal Transduction

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.

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Titre: Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas
Créateurs - sans rôle: Mark W Youngblood - Department of Neurological Surgery, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Zeynep Erson-Omay - Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
Chang Li - Department of Neurosurgery, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P. R. China
Hinda Najem - Department of Neurological Surgery, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Süleyman Coșkun - Department of Biological Sciences, Middle East Technical University, 06800, Ankara, Turkey
Evgeniya Tyrtova - Department of Neurosurgery, University of Washington, Seattle, WA, USA
Julio D Montejo - Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
Danielle F Miyagishima - Department of Genetics, Yale School of Medicine, New Haven, CT, USA
Tanyeri Barak - Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
Sayoko Nishimura - Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
Akdes Serin Harmancı - Department of Neurosurgery, Baylor College of Medicine, Houston, TX, 77030, USA
Victoria E Clark - Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
Daniel Duran - Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS, 39216, USA
Anita Huttner - Department of Pathology, Yale School of Medicine, New Haven, CT, USA
Timuçin Avşar - Department of Neurosurgery, Bahcesehir University, School of Medicine, Istanbul, Turkey
Yasar Bayri - Department of Neurosurgery, Marmara University School of Medicine, 34854, Istanbul, Turkey
Johannes Schramm - University of Bonn Medical School, 53105, Bonn, Germany
Julien Boetto - Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center, Montpellier, France
Matthieu Peyre - Department of Neurosurgery, Hopital Pitie-Salpetriere, AP-HP & Sorbonne Université, F-75103, Paris, France
Maximilien Riche - Department of Neurosurgery, Hopital Pitie-Salpetriere, AP-HP & Sorbonne Université, F-75103, Paris, France
Roland Goldbrunner - Center for Neurosurgery, University Hospital of Cologne, 50937, Cologne, Germany
Nduka Amankulor - Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA
Angeliki Louvi - Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
Kaya Bilgüvar - Department of Medical Genetics Acibadem Mehmet Ali Aydınlar University, School of Medicine, Istanbul, 34848, Turkey
M Necmettin Pamir - Department of Neurosurgery, Acibadem Mehmet Ali Aydınlar University, School of Medicine, Istanbul, 34848, Turkey
Koray Özduman - Department of Neurosurgery, Acibadem Mehmet Ali Aydınlar University, School of Medicine, Istanbul, 34848, Turkey
Türker Kilic - Department of Neurosurgery, Bahcesehir University, School of Medicine, Istanbul, Turkey
James R Knight - Yale Center for Genome Analysis, Yale University West Campus, Orange, CT, USA
Matthias Simon - Department of Neurosurgery, Bethel Clinic, University of Bielefeld Medical Center OWL, Bielefeld, Germany
Craig Horbinski - Department of Neurological Surgery, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Michel Kalamarides - Assistance Publique – Hôpitaux de Paris
Marco Timmer - Center for Neurosurgery, University Hospital of Cologne, 50937, Cologne, Germany
Amy B Heimberger - Department of Neurological Surgery, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Ketu Mishra-Gorur - Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
Jennifer Moliterno - Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
Katsuhito Yasuno - Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. katsuhito.yasuno@yale.edu
Murat Günel - Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu
Détails de publication: Nature communications, Vol.14(1), pp.6279-16
Note de subvention: F30 CA213666 / NCI NIH HHS P30 CA060553 / NCI NIH HHS P50 CA221747 / NCI NIH HHS T32 GM007205 / NIGMS NIH HHS F30 CA183530 / NCI NIH HHS R01 NS120547 / NINDS NIH HHS
Identifiants: 99163007809311
Unité académique: Institut de Génomique Fonctionnelle - IGF
Langue: English
Type de ressource: Journal article