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

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Youngblood M. W., Erson-Omay Z., Li C., Najem H., Coșkun S., Tyrtova E., ...More

Nature Communications, vol.14, no.1, 2023 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 14 Issue: 1
  • Publication Date: 2023
  • Doi Number: 10.1038/s41467-023-41926-y
  • Journal Name: Nature Communications
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Geobase, INSPEC, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Middle East Technical University Affiliated: No


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.