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

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), Cláudia P. Grou(University of Oxford), Garth Hamilton(University of Oxford), Nikola Vlahov(University of Oxford), Anna M. 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 Lü(University of Oxford), Francesca M. Buffa(University of Oxford), Grigory L. Dianov(University of Oxford), Alex von Kriegsheim(University College Dublin), David Matallanas(University College Dublin), Anastasia Samsonova(University of Oxford), Magdalena Zernicka‐Goetz(University of Cambridge), Eric O’Neill(University College Dublin)
Nature Communications
January 23, 2018
10.1038/s41467-017-02786-5
Cited by 101Open Access
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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.

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