TY - JOUR
T1 - YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis
AU - Pajtler, Kristian W.
AU - Wei, Yiju
AU - Okonechnikov, Konstantin
AU - Silva, Patricia B.G.
AU - Vouri, Mikaella
AU - Zhang, Lei
AU - Brabetz, Sebastian
AU - Sieber, Laura
AU - Gulley, Melissa
AU - Mauermann, Monika
AU - Wedig, Tatjana
AU - Mack, Norman
AU - Imamura Kawasawa, Yuka
AU - Sharma, Tanvi
AU - Zuckermann, Marc
AU - Andreiuolo, Felipe
AU - Holland, Eric
AU - Maass, Kendra
AU - Körkel-Qu, Huiqin
AU - Liu, Hai Kun
AU - Sahm, Felix
AU - Capper, David
AU - Bunt, Jens
AU - Richards, Linda J.
AU - Jones, David T.W.
AU - Korshunov, Andrey
AU - Chavez, Lukas
AU - Lichter, Peter
AU - Hoshino, Mikio
AU - Pfister, Stefan M.
AU - Kool, Marcel
AU - Li, Wei
AU - Kawauchi, Daisuke
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - https://www.mendeley.com/catalogue/84218922-dda3-37eb-8c0f-dd506106c48b/
U2 - 10.1038/s41467-019-11884-5
DO - 10.1038/s41467-019-11884-5
M3 - Article
C2 - 31477715
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3914
ER -