RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29382819.
- Also identified by DOI 10.1038/s41467-017-02786-5 and PMC identifier 5789973.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Adaptor Proteins, Signal Transducing
- Embryonic Stem Cells
- Phosphoproteins
- Protein Serine-Threonine Kinases
- Tumor Protein p73
- Tumor Suppressor Proteins