Lackner, Andreas ORCID: 0000-0003-1168-7947, Sehlke, Robert, Garmhausen, Marius ORCID: 0000-0002-8617-388X, Giuseppe Stirparo, Giuliano, Huth, Michelle ORCID: 0000-0002-1152-9140, Titz-Teixeira, Fabian ORCID: 0000-0002-7007-9039, van Der Lelij, Petra, Ramesmayer, Julia, Thomas, Henry F., Ralser, Meryem, Santini, Laura, Galimberti, Elena, Sarov, Mihail, Stewart, A. Francis, Smith, Austin, Beyer, Andreas ORCID: 0000-0002-3891-2123 and Leeb, Martin ORCID: 0000-0001-5114-4782 (2021). Cooperative genetic networks drive embryonic stem cell transition from naive to formative pluripotency. Embo J., 40 (8). HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

In the mammalian embryo, epiblast cells must exit the naive 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 naive 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 naive state exit. Transcriptome profiles for 73 ESC lines deficient for regulators of the exit from naive pluripotency predominantly manifest delays on the trajectory from naive 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 naive 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lackner, AndreasUNSPECIFIEDorcid.org/0000-0003-1168-7947UNSPECIFIED
Sehlke, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garmhausen, MariusUNSPECIFIEDorcid.org/0000-0002-8617-388XUNSPECIFIED
Giuseppe Stirparo, GiulianoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huth, MichelleUNSPECIFIEDorcid.org/0000-0002-1152-9140UNSPECIFIED
Titz-Teixeira, FabianUNSPECIFIEDorcid.org/0000-0002-7007-9039UNSPECIFIED
van Der Lelij, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramesmayer, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Henry F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ralser, MeryemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santini, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galimberti, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarov, MihailUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stewart, A. FrancisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, AustinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beyer, AndreasUNSPECIFIEDorcid.org/0000-0002-3891-2123UNSPECIFIED
Leeb, MartinUNSPECIFIEDorcid.org/0000-0001-5114-4782UNSPECIFIED
URN: urn:nbn:de:hbz:38-597089
DOI: 10.15252/embj.2020105776
Journal or Publication Title: Embo J.
Volume: 40
Number: 8
Date: 2021
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GROUND-STATE; SIGNALING PATHWAYS; SELF-RENEWAL; MOUSE; DERIVATION; INHIBITION; EXIT; MASS; DIFFERENTIATION; EXPLORATIONMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59708

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