RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73.
Papaspyropoulos A., Bradley L., Thapa A., Leung CY., Toskas K., Koennig D., Pefani D-E., Raso C., Grou C., Hamilton G., Vlahov N., Grawenda A., Haider S., Chauhan J., Buti L., Kanapin A., Lu X., Buffa F., Dianov G., von Kriegsheim A., Matallanas D., Samsonova A., Zernicka-Goetz M., O'Neill E.
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.