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RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73
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| Title: | RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73 | Authors: | Papaspyropoulos, Angelos; Bradley, Leanne; Thapa, Asmita; Raso, Cinzia; Kriegsheim, Alexander von; Matallanas, David; O'Neill, Eric; et al. | Permanent link: | http://hdl.handle.net/10197/11888 | Date: | 30-Jan-2018 | Online since: | 2021-01-26T07:18:12Z | 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. | Funding Details: | Science Foundation Ireland Wellcome Trust |
Funding Details: | CRUK A19277 MRC Pancreatic Cancer UK Federal Agency for Scientific Organizations |
Type of material: | Journal Article | Publisher: | Springer | Journal: | Nature Communications | Volume: | 9 | Copyright (published version): | 2018 the Authors | Keywords: | Protein-serine-threonine kinases; Adaptor proteins; DNA-binding proteins; Tumor suppressor proteins; Phosphoproteins; Transcription factors; Signal transduction; Cell differentiation; Gene expression regulation; Octamer transcription factor-3; Wnt proteins; Beta catenin; Basic helix-loop-helix transcription factors; Embryonic stem cells; Tumor protein p73; Signal transducing | DOI: | 10.1038/s41467-017-02786-5 | Language: | en | Status of Item: | Peer reviewed | ISSN: | 2041-1723 | This item is made available under a Creative Commons License: | https://creativecommons.org/licenses/by/3.0/ie/ |
| Appears in Collections: | SBI Research Collection Medicine Research Collection |
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