YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis

Kristian W. Pajtler, Yiju Wei, Konstantin Okonechnikov, Patricia B.G. Silva, Mikaella Vouri, Lei Zhang, Sebastian Brabetz, Laura Sieber, Melissa Gulley, Monika Mauermann, Tatjana Wedig, Norman Mack, Yuka Imamura Kawasawa, Tanvi Sharma, Marc Zuckermann, Felipe Andreiuolo, Eric Holland, Kendra Maass, Huiqin Körkel-Qu, Hai Kun LiuFelix Sahm, David Capper, Jens Bunt, Linda J. Richards, David T.W. Jones, Andrey Korshunov, Lukas Chavez, Peter Lichter, Mikio Hoshino, Stefan M. Pfister, Marcel Kool, Wei Li, Daisuke Kawauchi

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.

Original languageEnglish (US)
Article number3914
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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