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

• Published in: Nature communications Vol. 10; no. 1; pp. 3914 - 16
• Main Authors: Pajtler, Kristian W., Wei, Yiju, Okonechnikov, Konstantin, Silva, Patricia B. G., Vouri, Mikaella, Zhang, Lei, Brabetz, Sebastian, Sieber, Laura, Gulley, Melissa, Mauermann, Monika, Wedig, Tatjana, Mack, Norman, Imamura Kawasawa, Yuka, Sharma, Tanvi, Zuckermann, Marc, Andreiuolo, Felipe, Holland, Eric, Maass, Kendra, Körkel-Qu, Huiqin, Liu, Hai-Kun, Sahm, Felix, Capper, David, Bunt, Jens, Richards, Linda J., Jones, David T. W., Korshunov, Andrey, Chavez, Lukas, Lichter, Peter, Hoshino, Mikio, Pfister, Stefan M., Kool, Marcel, Li, Wei, Kawauchi, Daisuke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 14/19; 14/5; 38/23; 38/70; 49/15; 49/39; 49/91; 631/67/1922; 631/67/2332; 64/60; 692/4028; 82/29; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Binding sites; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Chromatin; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Ependymoma - genetics; Ependymoma - metabolism; Ependymoma - pathology; Genetic transformation; HEK293 Cells; Humanities and Social Sciences; Humans; Immunoprecipitation; Infants; Localization; Mice; Molecular modelling; multidisciplinary; Mutation; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; NFI Transcription Factors - genetics; NFI Transcription Factors - metabolism; NIH 3T3 Cells; Nuclear factor I; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Regulatory sequences; Science; Science (multidisciplinary); Subgroups; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumorigenesis; Tumors; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11884-5

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. The molecular mechanisms driving proliferation in the pediatric brain cancer epdendymoma are poorly understood. Here the authors show that a YAP1- MAMLD1 fusion drives tumor formation in mice and show that the fusion protein can collaborate with the TEAD and NFI transcription factors.