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A FGF2-mediated incoherent feedforward loop induces Erk inhibition and promotes naïve pluripotency

Borzo Gharibi, Emanuel Gonçalves, Buhe Nashun, Alex Montoya, Katherine Mankalow, Stephanie Strohbuecker, Rahuman S M Sheriff, Alessandro Cicarrelli, Joana Carvalho, Emma Nye, Holger Kramer, Ian Rosewell, Petra Hajkova, View ORCID ProfilePedro Beltrao, View ORCID ProfileSilvia D. M. Santos
doi: https://doi.org/10.1101/2020.11.11.378869
Borzo Gharibi
1The Francis Crick Institute, London, UK
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Emanuel Gonçalves
2Welcome Sanger Institute, Hinxton, Cambridge, UK
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Buhe Nashun
3MRC-London Institute of Medical Sciences, Imperial College London, London, UK
4School of Life Sciences, Inner Mongolia University, Hohhot, China
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Alex Montoya
3MRC-London Institute of Medical Sciences, Imperial College London, London, UK
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Katherine Mankalow
1The Francis Crick Institute, London, UK
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Stephanie Strohbuecker
1The Francis Crick Institute, London, UK
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Rahuman S M Sheriff
5European Molecular Biology Laboratory - European Bioinformatics Institute, EMBL-EBI, Hinxton, CA, UK
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Alessandro Cicarrelli
1The Francis Crick Institute, London, UK
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Joana Carvalho
1The Francis Crick Institute, London, UK
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Emma Nye
1The Francis Crick Institute, London, UK
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Holger Kramer
3MRC-London Institute of Medical Sciences, Imperial College London, London, UK
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Ian Rosewell
1The Francis Crick Institute, London, UK
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Petra Hajkova
3MRC-London Institute of Medical Sciences, Imperial College London, London, UK
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Pedro Beltrao
5European Molecular Biology Laboratory - European Bioinformatics Institute, EMBL-EBI, Hinxton, CA, UK
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  • ORCID record for Pedro Beltrao
Silvia D. M. Santos
1The Francis Crick Institute, London, UK
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  • ORCID record for Silvia D. M. Santos
  • For correspondence: silvia.santos@crick.ac.uk
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Abstract

Naïve pluripotency is a transient state during mammalian development that can be recapitulated indefinitely in vitro by inhibition of the mitogen-activated protein kinase (MAPK/Erk) signalling and activation of STAT and Wnt pathways. How Erk is inhibited in vivo to promote naïve pluripotency remains largely unknown. By combining live cell imaging and quantitative proteomics we found that FGF2, a known Erk activator and pro-differentiation cue, induces instead long-term Erk inhibition in both ES cells and mouse embryos. We show that Erk inhibition results from a FGF2-induced incoherent feedforward loop. Importantly, we see that FGF2 induces up-regulation of naïve pluripotency factors, down-regulation of DNA methylation by suppression of de novo DNA methylases thereby helping maintain naïve pluripotency. We show that FGF2 is expressed maternally and propose that integration of signals from the embryo’s niche may contribute to the generation of embryonic lineages with the right cell proportions. We suggest that feedforward regulation may play a role driving transient, reversible developmental transitions.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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A FGF2-mediated incoherent feedforward loop induces Erk inhibition and promotes naïve pluripotency
Borzo Gharibi, Emanuel Gonçalves, Buhe Nashun, Alex Montoya, Katherine Mankalow, Stephanie Strohbuecker, Rahuman S M Sheriff, Alessandro Cicarrelli, Joana Carvalho, Emma Nye, Holger Kramer, Ian Rosewell, Petra Hajkova, Pedro Beltrao, Silvia D. M. Santos
bioRxiv 2020.11.11.378869; doi: https://doi.org/10.1101/2020.11.11.378869
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A FGF2-mediated incoherent feedforward loop induces Erk inhibition and promotes naïve pluripotency
Borzo Gharibi, Emanuel Gonçalves, Buhe Nashun, Alex Montoya, Katherine Mankalow, Stephanie Strohbuecker, Rahuman S M Sheriff, Alessandro Cicarrelli, Joana Carvalho, Emma Nye, Holger Kramer, Ian Rosewell, Petra Hajkova, Pedro Beltrao, Silvia D. M. Santos
bioRxiv 2020.11.11.378869; doi: https://doi.org/10.1101/2020.11.11.378869

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