RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73
| Autor: | Papaspyropoulos, Angelos, Bradley, Leanne, Thapa, Asmita, Raso, Cinzia, Kriegsheim, Alexander von, Matallanas, David, O'Neill, Eric |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Gene expression regulation
endocrine system Protein-serine-threonine kinases Embryonic stem cells Tumor protein p73 Beta catenin Signal transduction Phosphoproteins Signal transducing Wnt proteins Tumor suppressor proteins Basic helix-loop-helix transcription factors Adaptor proteins DNA-binding proteins Transcription factors Cell differentiation Octamer transcription factor-3 |
| Popis: | 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. Science Foundation Ireland Wellcome Trust CRUK A19277 MRC Pancreatic Cancer UK Federal Agency for Scientific Organizations |
| Databáze: | OpenAIRE |
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