RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated 2 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; Anna Grawenda; Syed Haider; Jagat Chauhan; Ludovico Buti; Alexander Kanapin; Xin Lu; Francesca M Buffa; Grigory  Dianov; Alex Von Kriegsheim; David Matallanas; Anastasia Samsonova; Magdalena Zernicka-Goetz; Eric O'Neill

doi:10.1038/s41467-017-02786-5

RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated 2 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, Anna Grawenda, Syed Haider, Jagat Chauhan, Ludovico Buti, Alexander Kanapin, Xin Lu, Francesca M Buffa, Grigory Dianov, Alex Von Kriegsheim, David MatallanasAnastasia Samsonova, Magdalena Zernicka-Goetz, Eric O'Neill

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Nature Communications
Early online date	30 Jan 2018
DOIs	https://doi.org/10.1038/s41467-017-02786-5
Publication status	E-pub ahead of print - 30 Jan 2018

Keywords

Cell signalling
Embryonic stem cells
Pluipotency

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10.1038/s41467-017-02786-5

RASSF1A
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Papaspyropoulos, A., Bradley, L., Thapa, A., Leung, C. Y., Toskas, K., Koennig, D., Pefani, D-E., Raso, C., Grou, C., Hamilton, G., Grawenda, A., Haider, S., Chauhan, J., Buti, L., Kanapin, A., Lu, X., Buffa, F. M., Dianov, G., Von Kriegsheim, A., ... O'Neill, E. (2018). RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated 2 differentiation via p73. Nature Communications. https://doi.org/10.1038/s41467-017-02786-5

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title = "RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated 2 differentiation via p73",

abstract = "Transition from pluripotency to differentiation is a pivotal yet poorly understooddevelopmental 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 Oct4distal 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.",

keywords = "Cell signalling, Embryonic stem cells, Pluipotency",

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

year = "2018",

month = jan,

day = "30",

doi = "10.1038/s41467-017-02786-5",

language = "English",

journal = "Nature Communications",

issn = "2041-1723",

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Papaspyropoulos, A, Bradley, L, Thapa, A, Leung, CY, Toskas, K, Koennig, D, Pefani, D-E, Raso, C, Grou, C, Hamilton, G, Grawenda, A, Haider, S, Chauhan, J, Buti, L, Kanapin, A, Lu, X, Buffa, FM, 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 2 differentiation via p73', Nature Communications. https://doi.org/10.1038/s41467-017-02786-5

TY - JOUR

T1 - RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated 2 differentiation via p73

AU - Papaspyropoulos, Angelos

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 - Grawenda, Anna

AU - Haider, Syed

AU - Chauhan, Jagat

AU - Buti, Ludovico

AU - Kanapin, Alexander

AU - Lu, Xin

AU - Buffa, Francesca M

AU - Dianov, Grigory

AU - Von Kriegsheim, Alex

AU - Matallanas, David

AU - Samsonova, Anastasia

AU - Zernicka-Goetz, Magdalena

AU - O'Neill, Eric

PY - 2018/1/30

Y1 - 2018/1/30

N2 - Transition from pluripotency to differentiation is a pivotal yet poorly understooddevelopmental 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 Oct4distal 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.

AB - Transition from pluripotency to differentiation is a pivotal yet poorly understooddevelopmental 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 Oct4distal 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.

KW - Cell signalling

KW - Embryonic stem cells

KW - Pluipotency

U2 - 10.1038/s41467-017-02786-5

DO - 10.1038/s41467-017-02786-5

M3 - Article

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

ER -

RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated 2 differentiation via p73

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Keywords

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