Repository logo
 

Cooperative genetic networks drive embryonic stem cell transition from naïve to formative pluripotency.

Published version
Peer-reviewed

Change log

Authors

Sehlke, Robert 
Giuseppe Stirparo, Giuliano  ORCID logo  https://orcid.org/0000-0002-5911-8682

Abstract

In the mammalian embryo, epiblast cells must exit the naïve state and acquire formative pluripotency. This cell state transition is recapitulated by mouse embryonic stem cells (ESCs), which undergo pluripotency progression in defined conditions in vitro. However, our understanding of the molecular cascades and gene networks involved in the exit from naïve pluripotency remains fragmentary. Here, we employed a combination of genetic screens in haploid ESCs, CRISPR/Cas9 gene disruption, large-scale transcriptomics and computational systems biology to delineate the regulatory circuits governing naïve state exit. Transcriptome profiles for 73 ESC lines deficient for regulators of the exit from naïve pluripotency predominantly manifest delays on the trajectory from naïve to formative epiblast. We find that gene networks operative in ESCs are also active during transition from pre- to post-implantation epiblast in utero. We identified 496 naïve state-associated genes tightly connected to the in vivo epiblast state transition and largely conserved in primate embryos. Integrated analysis of mutant transcriptomes revealed funnelling of multiple gene activities into discrete regulatory modules. Finally, we delineate how intersections with signalling pathways direct this pivotal mammalian cell state transition.

Description

Keywords

exit from naïve pluripotency, haploid ES cells, naïve to formative transition, signalling, systems biology, Animals, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Mice, Mouse Embryonic Stem Cells, Transcriptome

Journal Title

EMBO J

Conference Name

Journal ISSN

0261-4189
1460-2075

Volume Title

40

Publisher

Springer Science and Business Media LLC
Sponsorship
Vienna Science and Technology Fund (WWTF) (VRG14‐006)
Austrian Science Fund (FWF) (I 3786)
Deutsche Forschungsgemeinschaft (DFG) (398882498)
FP7 Health (HEALTH) (242129)
Medical Research Council ((MR/P00072X/1))