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

Andreas Lackner; Robert Sehlke; Marius Garmhausen; Giuliano Giuseppe Stirparo; Michelle Huth; Fabian Titz‐Teixeira; Petra Lelij; Julia Ramesmayer; Henry F Thomas; Meryem Ralser; Laura Santini; Elena Galimberti; Mihail Sarov; A Francis Stewart; Austin Smith; Andreas Beyer; Martin Leeb

doi:10.15252/embj.2020105776

Titel

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

Autor*in

Andreas Lackner

Zentrum für Molekulare Biologie (bis 2023-12-31), Universität Wien

Robert Sehlke

Cologne Excellence Cluster Cellular Stress Response in Aging‐Associated Diseases (CECAD), University of Cologne

Marius Garmhausen

Cologne Excellence Cluster Cellular Stress Response in Aging‐Associated Diseases (CECAD), University of Cologne

... show all

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.

Stichwort

exit from naïve pluripotencyhaploid ES cellsnaïve to formative transitionsignallingsystems biology

Objekt-Typ

journal article

Sprache

Englisch [eng]

Persistent identifier

phaidra.univie.ac.at/o:1437422

DOI

10.15252/embj.2020105776

Erschienen in

Titel