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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 \u03b2-catenin-TCF pluripotency network to a key factor that promotes differentiation. We demonstrate that epigenetic regulation of the <jats:italic>Rassf1A<\/jats:italic> promoter maintains stemness by allowing a quaternary association of YAP\u2013TEAD and \u03b2-catenin\u2013TCF3 complexes on the <jats:italic>Oct4<\/jats:italic> distal enhancer. However, during differentiation, promoter demethylation allows GATA1-mediated RASSF1A expression which prevents YAP from contributing to the TEAD\/\u03b2-catenin\u2013TCF3 complex. Simultaneously, we find that RASSF1A promotes a YAP\u2013p73 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 \u201cswitch\u201d between pluripotency and initiation of differentiation.<\/jats:p>","DOI":"10.1038\/s41467-017-02786-5","type":"journal-article","created":{"date-parts":[[2018,1,23]],"date-time":"2018-01-23T23:22:03Z","timestamp":1516749723000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73"],"prefix":"10.1038","volume":"9","author":[{"given":"Angelos","family":"Papaspyropoulos","sequence":"first","affiliation":[]},{"given":"Leanne","family":"Bradley","sequence":"additional","affiliation":[]},{"given":"Asmita","family":"Thapa","sequence":"additional","affiliation":[]},{"given":"Chuen Yan","family":"Leung","sequence":"additional","affiliation":[]},{"given":"Konstantinos","family":"Toskas","sequence":"additional","affiliation":[]},{"given":"Delia","family":"Koennig","sequence":"additional","affiliation":[]},{"given":"Dafni-Eleftheria","family":"Pefani","sequence":"additional","affiliation":[]},{"given":"Cinzia","family":"Raso","sequence":"additional","affiliation":[]},{"given":"Claudia","family":"Grou","sequence":"additional","affiliation":[]},{"given":"Garth","family":"Hamilton","sequence":"additional","affiliation":[]},{"given":"Nikola","family":"Vlahov","sequence":"additional","affiliation":[]},{"given":"Anna","family":"Grawenda","sequence":"additional","affiliation":[]},{"given":"Syed","family":"Haider","sequence":"additional","affiliation":[]},{"given":"Jagat","family":"Chauhan","sequence":"additional","affiliation":[]},{"given":"Ludovico","family":"Buti","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9802-5297","authenticated-orcid":false,"given":"Alexander","family":"Kanapin","sequence":"additional","affiliation":[]},{"given":"Xin","family":"Lu","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0409-406X","authenticated-orcid":false,"given":"Francesca","family":"Buffa","sequence":"additional","affiliation":[]},{"given":"Grigory","family":"Dianov","sequence":"additional","affiliation":[]},{"given":"Alex","family":"von Kriegsheim","sequence":"additional","affiliation":[]},{"given":"David","family":"Matallanas","sequence":"additional","affiliation":[]},{"given":"Anastasia","family":"Samsonova","sequence":"additional","affiliation":[]},{"given":"Magdalena","family":"Zernicka-Goetz","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0060-6278","authenticated-orcid":false,"given":"Eric","family":"O\u2019Neill","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2018,1,30]]},"reference":[{"key":"2786_CR1","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/j.cell.2005.08.020","volume":"122","author":"LA Boyer","year":"2005","unstructured":"Boyer, L. 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