Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1038/s41467-017-02786-5

Type

Journal article

Journal

Nat Commun

Publication Date

30/01/2018

Volume

9

Keywords

Adaptor Proteins, Signal Transducing, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, DNA-Binding Proteins, Embryonic Stem Cells, Female, Gene Expression Regulation, Developmental, Humans, Male, Mice, Inbred C57BL, Mice, Inbred CBA, Octamer Transcription Factor-3, Phosphoproteins, Protein-Serine-Threonine Kinases, Signal Transduction, Transcription Factors, Tumor Protein p73, Tumor Suppressor Proteins, Wnt Proteins, beta Catenin