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 Liu; Felix 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

doi:10.1038/s41467-019-11884-5

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

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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.

Originele taal-2	Engels
Artikelnummer	3914
Tijdschrift	Nature communications
Volume	10
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1038/s41467-019-11884-5
Status	Gepubliceerd - 1 dec. 2019
Extern gepubliceerd	Ja

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Pajtler, K. W., Wei, Y., Okonechnikov, K., Silva, P. B. G., Vouri, M., Zhang, L., Brabetz, S., Sieber, L., Gulley, M., Mauermann, M., Wedig, T., Mack, N., Imamura Kawasawa, Y., Sharma, T., Zuckermann, M., Andreiuolo, F., Holland, E., Maass, K., Körkel-Qu, H., ... Kawauchi, D. (2019). YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis. Nature communications, 10(1), Artikel 3914. https://doi.org/10.1038/s41467-019-11884-5

@article{395af56ff09d497897cafb73db2ec1ca,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-11884-5",

language = "English",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Pajtler, KW, Wei, Y, Okonechnikov, K, Silva, PBG, Vouri, M, Zhang, L, Brabetz, S, Sieber, L, Gulley, M, Mauermann, M, Wedig, T, Mack, N, Imamura Kawasawa, Y, Sharma, T, Zuckermann, M, Andreiuolo, F, Holland, E, Maass, K, Körkel-Qu, H, Liu, HK, Sahm, F, Capper, D, Bunt, J, Richards, LJ, Jones, DTW, Korshunov, A, Chavez, L, Lichter, P, Hoshino, M, Pfister, SM, Kool, M, Li, W & Kawauchi, D 2019, 'YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis', Nature communications, vol. 10, nr. 1, 3914. https://doi.org/10.1038/s41467-019-11884-5

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

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 -

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

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