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

Angelos Papaspyropoulos, Leanne Bradley, Asmita Thapa, Chuen Yan Leung, Konstantinos Toskas, Delia Koennig, Dafni-Eleftheria Pefani, Cinzia Raso, Claudia Grou, Garth Hamilton, Nikola Vlahov, Anna Grawenda, Syed Haider, Jagat Chauhan, Ludovico Buti, Alexander Kanapin, Xin Lu, Francesca Buffa, Grigory Dianov, Alex Kriegsheim, David Matallanas, Anastasia Samsonova, Magdalena Zernicka-Goetz and Eric O’Neill ()
Additional contact information
Angelos Papaspyropoulos: University of Oxford
Leanne Bradley: University of Oxford
Asmita Thapa: University of Oxford
Chuen Yan Leung: 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
Alex Kriegsheim: University College Dublin
David Matallanas: University College Dublin
Anastasia Samsonova: University of Oxford
Magdalena Zernicka-Goetz: University of Cambridge
Eric O’Neill: University of Oxford

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02786-5

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DOI: 10.1038/s41467-017-02786-5

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