RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated 2 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, Anna Grawenda, Syed Haider, Jagat Chauhan, Ludovico Buti, Alexander Kanapin, Xin Lu, Francesca M Buffa, Grigory Dianov, Alex Von Kriegsheim, David MatallanasAnastasia Samsonova, Magdalena Zernicka-Goetz, Eric O'Neill

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
JournalNature Communications
Early online date30 Jan 2018
Publication statusE-pub ahead of print - 30 Jan 2018


  • Cell signalling
  • Embryonic stem cells
  • Pluipotency


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