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A novel Nodal enhancer dependent on pluripotency factors and Smad2/3 signaling conditions a regulatory switch during epiblast maturation
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Papanayotou, Costis, Benhaddou, Ataaillah, Camus, Anne, Perea-Gomez, Aitana, Jouneau, Alice, Mezger, Valérie, Langa, Francina, Ott, Sascha, Sabéran-Djoneidi, Délara and Collignon, Jérôme (2014) A novel Nodal enhancer dependent on pluripotency factors and Smad2/3 signaling conditions a regulatory switch during epiblast maturation. PLoS Biology, Volume 12 (Number 6). Article number e1001890. doi:10.1371/journal.pbio.1001890 ISSN 1545-7885.
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Official URL: http://dx.doi.org/10.1371/journal.pbio.1001890
Abstract
During early development, modulations in the expression of Nodal, a TGFβ family member, determine the specification of embryonic and extra-embryonic cell identities. Nodal has been extensively studied in the mouse, but aspects of its early expression remain unaccounted for. We identified a conserved hotspot for the binding of pluripotency factors at the Nodal locus and called this sequence “highly bound element” (HBE). Luciferase-based assays, the analysis of fluorescent HBE reporter transgenes, and a conditional mutation of HBE allowed us to establish that HBE behaves as an enhancer, is activated ahead of other Nodal enhancers in the epiblast, and is essential to Nodal expression in embryonic stem cells (ESCs) and in the mouse embryo. We also showed that HBE enhancer activity is critically dependent on its interaction with the pluripotency factor Oct4 and on Activin/Nodal signaling. Use of an in vitro model of epiblast maturation, relying on the differentiation of ESCs into epiblast stem cells (EpiSCs), revealed that this process entails a shift in the regulation of Nodal expression from an HBE-driven phase to an ASE-driven phase, ASE being another autoregulatory Nodal enhancer. Deletion of HBE in ESCs or in EpiSCs allowed us to show that HBE, although not necessary for Nodal expression in EpiSCs, is required in differentiating ESCs to activate the differentiation-promoting ASE and therefore controls this regulatory shift. Our findings clarify how early Nodal expression is regulated and suggest how this regulation can promote the specification of extra-embryonic precusors without inducing premature differentiation of epiblast cells. More generally, they open new perspectives on how pluripotency factors achieve their function.
Item Type: | Journal Article | ||||||||
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Subjects: | Q Science > QH Natural history > QH426 Genetics Q Science > QL Zoology Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Research Centres > Warwick Systems Biology Centre | ||||||||
Library of Congress Subject Headings (LCSH): | Embryonic stem cells, Fibroblast growth factors, Gene regulatory networks, Embryos | ||||||||
Journal or Publication Title: | PLoS Biology | ||||||||
Publisher: | Public Library of Science | ||||||||
ISSN: | 1545-7885 | ||||||||
Official Date: | 24 June 2014 | ||||||||
Dates: |
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Volume: | Volume 12 | ||||||||
Number: | Number 6 | ||||||||
Article Number: | Article number e1001890 | ||||||||
DOI: | 10.1371/journal.pbio.1001890 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||
Date of first compliant deposit: | 27 December 2015 | ||||||||
Date of first compliant Open Access: | 27 December 2015 | ||||||||
Funder: | Fondation pour la recherche médicale (FRM), France. Agence nationale de la recherche (ANR), StemPole-IdF, Ligue nationale contre le cancer (France) (LNCC) |
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