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RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73

Author

Listed:
  • Angelos Papaspyropoulos

    (University of Oxford)

  • Leanne Bradley

    (University of Oxford)

  • Asmita Thapa

    (University of Oxford)

  • Chuen Yan Leung

    (University of Cambridge
    University of Cambridge)

  • Konstantinos Toskas

    (University of Oxford)

  • Delia Koennig

    (University of Oxford)

  • Dafni-Eleftheria Pefani

    (University of Oxford)

  • Cinzia Raso

    (University College Dublin)

  • Claudia Grou

    (University of Oxford)

  • Garth Hamilton

    (University of Oxford)

  • Nikola Vlahov

    (University of Oxford)

  • Anna Grawenda

    (University of Oxford)

  • Syed Haider

    (University of Oxford)

  • Jagat Chauhan

    (University of Oxford)

  • Ludovico Buti

    (University of Oxford)

  • Alexander Kanapin

    (University of Oxford)

  • Xin Lu

    (University of Oxford)

  • Francesca Buffa

    (University of Oxford)

  • Grigory Dianov

    (University of Oxford
    Institute of Cytology and Genetics, Russian Academy of Sciences)

  • Alex Kriegsheim

    (University College Dublin)

  • David Matallanas

    (University College Dublin)

  • Anastasia Samsonova

    (University of Oxford)

  • Magdalena Zernicka-Goetz

    (University of Cambridge
    University of Cambridge)

  • Eric O’Neill

    (University of Oxford
    University College Dublin)

Abstract

Transition from pluripotency to differentiation is a pivotal yet poorly understood developmental step. Here, we show that the tumour suppressor RASSF1A is a key player driving the early specification of cell fate. RASSF1A acts as a natural barrier to stem cell self-renewal and iPS cell generation, by switching YAP from an integral component in the β-catenin-TCF pluripotency network to a key factor that promotes differentiation. We demonstrate that epigenetic regulation of the Rassf1A promoter maintains stemness by allowing a quaternary association of YAP–TEAD and β-catenin–TCF3 complexes on the Oct4 distal enhancer. However, during differentiation, promoter demethylation allows GATA1-mediated RASSF1A expression which prevents YAP from contributing to the TEAD/β-catenin–TCF3 complex. Simultaneously, we find that RASSF1A promotes a YAP–p73 transcriptional programme that enables differentiation. Together, our findings demonstrate that RASSF1A mediates transcription factor selection of YAP in stem cells, thereby acting as a functional “switch” between pluripotency and initiation of differentiation.

Suggested Citation

  • Angelos Papaspyropoulos & Leanne Bradley & Asmita Thapa & Chuen Yan Leung & Konstantinos Toskas & Delia Koennig & Dafni-Eleftheria Pefani & Cinzia Raso & Claudia Grou & Garth Hamilton & Nikola Vlahov , 2018. "RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02786-5
    DOI: 10.1038/s41467-017-02786-5
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    Cited by:

    1. Marilyn Goudreault & Valérie Gagné & Chang Hwa Jo & Swati Singh & Ryan C. Killoran & Anne-Claude Gingras & Matthew J. Smith, 2022. "Afadin couples RAS GTPases to the polarity rheostat Scribble," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Yabo Zhou & Dianheng Wang & Li Zhou & Nannan Zhou & Zhenfeng Wang & Jie Chen & Ruiyang Pang & Haixia Fu & Qiusha Huang & Fang Dong & Hui Cheng & Huafeng Zhang & Ke Tang & Jingwei Ma & Jiadi Lv & Tao C, 2024. "Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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