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., Coskun S., Tyrtova E., ...Daha Fazla

NATURE COMMUNICATIONS, cilt.14, sa.1, 2023 (SCI-Expanded) identifier identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 14 Sayı: 1
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1038/s41467-023-41926-y
  • Dergi Adı: NATURE COMMUNICATIONS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Geobase, INSPEC, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Evet

Özet

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. Hedgehog signalling is known to be linked to oncogenic proliferation. Here, the authors identify structural events as a mechanism of Hedgehog activation in over one-third of driver unknown meningiomas.