RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73

Angelos Papaspyropoulos, Leanne Bradley, Asmita Thapa, Chuen Yan Leung, Konstantinos Toskas, Delia Koennig, Dafni Eleftheria Pefani, Cinzia Raso, Claudia Grou, Garth Hamilton, Nikola Vlahov, Anna Grawenda, Syed Haider, Jagat Chauhan, Ludovico Buti, Alexander Kanapin, Xin Lu, Francesca Buffa, Grigory Dianov, Alex Von KriegsheimDavid Matallanas, Anastasia Samsonova, Magdalena Zernicka-Goetz, Eric O'Neill

Research output

15 Citations (Scopus)

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 beta-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 beta-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/beta-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 languageEnglish
Article number424
Pages (from-to)424
Number of pages15
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 30 Jan 2018

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beta Catenin
Stem cells
stem cells
Epigenomics
Tumors
Transcription Factors
Stem Cells
suppressors
Switches
Specifications
cells
specifications
tumors
switches
Neoplasms

Cite this

Papaspyropoulos, A., Bradley, L., Thapa, A., Leung, C. Y., Toskas, K., Koennig, D., ... O'Neill, E. (2018). RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73. Nature Communications, 9(1), 424. [424]. https://doi.org/10.1038/s41467-017-02786-5
Papaspyropoulos, Angelos ; Bradley, Leanne ; Thapa, Asmita ; Leung, Chuen Yan ; Toskas, Konstantinos ; Koennig, Delia ; Pefani, Dafni Eleftheria ; Raso, Cinzia ; Grou, Claudia ; Hamilton, Garth ; Vlahov, Nikola ; Grawenda, Anna ; Haider, Syed ; Chauhan, Jagat ; Buti, Ludovico ; Kanapin, Alexander ; Lu, Xin ; Buffa, Francesca ; Dianov, Grigory ; Von Kriegsheim, Alex ; Matallanas, David ; Samsonova, Anastasia ; Zernicka-Goetz, Magdalena ; O'Neill, Eric. / RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73. In: Nature Communications. 2018 ; Vol. 9, No. 1. pp. 424.
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Papaspyropoulos, A, Bradley, L, Thapa, A, Leung, CY, Toskas, K, Koennig, D, Pefani, DE, Raso, C, Grou, C, Hamilton, G, Vlahov, N, Grawenda, A, Haider, S, Chauhan, J, Buti, L, Kanapin, A, Lu, X, Buffa, F, Dianov, G, Von Kriegsheim, A, Matallanas, D, Samsonova, A, Zernicka-Goetz, M & O'Neill, E 2018, 'RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73', Nature Communications, vol. 9, no. 1, 424, pp. 424. https://doi.org/10.1038/s41467-017-02786-5

RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73. / Papaspyropoulos, Angelos; Bradley, Leanne; Thapa, Asmita; Leung, Chuen Yan; Toskas, Konstantinos; Koennig, Delia; Pefani, Dafni Eleftheria; Raso, Cinzia; Grou, Claudia; Hamilton, Garth; Vlahov, Nikola; Grawenda, Anna; Haider, Syed; Chauhan, Jagat; Buti, Ludovico; Kanapin, Alexander; Lu, Xin; Buffa, Francesca; Dianov, Grigory; Von Kriegsheim, Alex; Matallanas, David; Samsonova, Anastasia; Zernicka-Goetz, Magdalena; O'Neill, Eric.

In: Nature Communications, Vol. 9, No. 1, 424, 30.01.2018, p. 424.

Research output

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AU - Bradley, Leanne

AU - Thapa, Asmita

AU - Leung, Chuen Yan

AU - Toskas, Konstantinos

AU - Koennig, Delia

AU - Pefani, Dafni Eleftheria

AU - Raso, Cinzia

AU - Grou, Claudia

AU - Hamilton, Garth

AU - Vlahov, Nikola

AU - Grawenda, Anna

AU - Haider, Syed

AU - Chauhan, Jagat

AU - Buti, Ludovico

AU - Kanapin, Alexander

AU - Lu, Xin

AU - Buffa, Francesca

AU - Dianov, Grigory

AU - Von Kriegsheim, Alex

AU - Matallanas, David

AU - Samsonova, Anastasia

AU - Zernicka-Goetz, Magdalena

AU - O'Neill, Eric

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AB - 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 beta-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 beta-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/beta-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.

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KW - PREIMPLANTATION MOUSE DEVELOPMENT

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KW - TGF-BETA

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KW - PATHWAY

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Papaspyropoulos A, Bradley L, Thapa A, Leung CY, Toskas K, Koennig D et al. RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73. Nature Communications. 2018 Jan 30;9(1):424. 424. https://doi.org/10.1038/s41467-017-02786-5