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

Autor: Petra van der Lelij, Laura Santini, Henry Fabian Thomas, Meryem Ralser, Elena Galimberti, Mihail Sarov, Marius Garmhausen, Martin Leeb, Andreas Beyer, Giuliano Giuseppe Stirparo, A. Francis Stewart, Fabian Titz-Teixeira, Robert Sehlke, Julia Ramesmayer, Andreas Lackner, Michelle Huth, Austin Smith
Přispěvatelé: Lackner, Andreas [0000-0003-1168-7947], Garmhausen, Marius [0000-0002-8617-388X], Giuseppe Stirparo, Giuliano [0000-0002-5911-8682], Huth, Michelle [0000-0002-1152-9140], Titz-Teixeira, Fabian [0000-0002-7007-9039], van der Lelij, Petra [0000-0002-7461-9645], Santini, Laura [0000-0001-9968-2459], Smith, Austin [0000-0002-3029-4682], Beyer, Andreas [0000-0002-3891-2123], Leeb, Martin [0000-0001-5114-4782], Apollo - University of Cambridge Repository
Rok vydání: 2021
Předmět:
Resource
animal structures
haploid ES cells
Systems biology
Gene regulatory network
Methods & Resources
Biology
Regenerative Medicine
Chromatin
Epigenetics
Genomics & Functional Genomics
General Biochemistry
Genetics and Molecular Biology
Transcriptome
Mice
03 medical and health sciences
0302 clinical medicine
Animals
CRISPR
Gene Regulatory Networks
signalling
Molecular Biology
Gene
Cells
Cultured
reproductive and urinary physiology
030304 developmental biology
0303 health sciences
General Immunology and Microbiology
General Neuroscience
Gene Expression Regulation
Developmental
systems biology
Cell Differentiation
Mouse Embryonic Stem Cells
naïve to formative transition
Embryonic stem cell
Cell biology
Epiblast
exit from naïve pluripotency
embryonic structures
030217 neurology & neurosurgery
Genetic screen
Zdroj: The EMBO Journal
ISSN: 1460-2075
0261-4189
Popis: 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.
An extensive mutagenesis screen identifies regulatory gene modules governing exit from naïve mammalian pluripotency.
Databáze: OpenAIRE
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