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

Papaspyropoulos, Angelos and Bradley, Leanne and Thapa, Asmita and Leung, Chuen Yan and Toskas, Konstantinos and Koennig, Delia and Pefani, Dafni-Eleftheria and Raso, Cinzia and Grou, Claudia and Hamilton, Garth and Vlahov, Nikola and Grawenda, Anna and Haider, Syed and Chauhan, Jagat and Buti, Ludovico and Kanapin, Alexander and Lu, Xin and Buffa, Francesca and Dianov, Grigory and von Kriegsheim, Alex and Matallanas, David and Samsonova, Anastasia and Zernicka-Goetz, Magdalena and O’Neill, Eric (2018) RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73. Nature Communications, 9 . Art. No. 424. ISSN 2041-1723. PMCID PMC5789973. doi:10.1038/s41467-017-02786-5.

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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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URLURL TypeDescription CentralArticle
Chauhan, Jagat0000-0003-0330-1901
Kanapin, Alexander0000-0001-9802-5297
Buffa, Francesca0000-0003-0409-406X
Zernicka-Goetz, Magdalena0000-0002-7004-2471
O’Neill, Eric0000-0002-0060-6278
Additional Information:© The Author(s) 2018. Open Access - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Received: 15 March 2017. Accepted: 29 December 2017. Published online: 30 January 2018. We thank L. van der Weyden for MEFs and Dr P. Liu for his valuable input regarding somatic cell reprogramming. We also thank Prof Hans Clevers, Prof Colin Goding, Dr Skirmantas Kriaucionis and Dr Vincenzo D’Angiolella for reading this manuscript. This work is supported by CRUK A19277, MRC, Pancreatic Cancer UK, the Federal Agency for Scientific Organizations (FASO Russia grant N° 0324-2016-0008), the Wellcome Trust and the Science Foundation Ireland (grant N° 15/CDA/3495). Author Contributions: A.P. and E.O.N. designed the study, designed and performed experiments, analysed and interpreted data. L.B., A.T., C.Y.L., K.T., D.K., D-E.P., C.R., C.G. and A.v.K. performed experiments and analysed data. A.G., S.H., J.C., A.K., F.B., D.M. and A.S. analysed data. G.H., N.V. and L.B. contributed to research tools. X.L., G.D., D.M. and M.Z-G. also helped with the study design and data interpretation. A.P. and E.O.N. wrote the manuscript and E.O.N. supervised the project. Data availability statement: Published GEO data sets are analysed in Figs. 1, 5 and Supplementary Fig. 7. These have the following accession codes: In Fig. 1—GSE54186, GSE3749, GDS2672; in Fig. 5—GDS3599, GDS2156, GDS752, GDS814 and GDS3599, GDS1824, GSE54186, GDS2156 were also discussed in Supplementary Fig. 7. The authors declare that all data supporting the findings of this study are available within the article and its supplementary information files or from the corresponding author upon reasonable request. The authors declare no competing financial interests.
Funding AgencyGrant Number
Cancer Research UKA19277
Medical Research Council (UK)UNSPECIFIED
Pancreatic Cancer UKUNSPECIFIED
Federal Agency for Scientific Organizations (Russia)0324-2016-0008
Science Foundation, Ireland15/CDA/3495
PubMed Central ID:PMC5789973
Record Number:CaltechAUTHORS:20190408-111046546
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94569
Deposited By: George Porter
Deposited On:09 Apr 2019 14:50
Last Modified:16 Nov 2021 17:06

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