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RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73
Date Issued
2018-01-30
Date Available
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.
Sponsorship
Science Foundation Ireland
Wellcome Trust
Other Sponsorship
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-threon...
Adaptor proteins
DNA-binding proteins
Tumor suppressor prot...
Phosphoproteins
Transcription factors...
Signal transduction
Cell differentiation
Gene expression regul...
Octamer transcription...
Wnt proteins
Beta catenin
Basic helix-loop-heli...
Embryonic stem cells
Tumor protein p73
Signal transducing
Language
English
Status of Item
Peer reviewed
ISSN
2041-1723
This item is made available under a Creative Commons License
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RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73.pdf
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