| Autor: |
Martin Leeb, Robert Sehlke, Petra van der Lelij, A. Francis Stewart, Marius Garmhausen, Mihail Sarov, Andreas Lackner, Henry Fabian Thomas, Julia Ramesmayer, Laura Santini, Andreas Beyer, Michelle Huth, Fabian Titz-Teixeira, Austin Smith, Giuliano Giuseppe Stirparo, Meryem Ralser |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
In the mammalian embryo, epiblast cells must exit their 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 fragmented. 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 knockout ESC lines predominantly manifest delays on the trajectory from naive to formative epiblast. We find that gene networks operative in ESCs are active during transition from pre- to post-implantation epiblast in utero. We identified 374 naïve-associated genes tightly connected to epiblast state and largely conserved in human ESCs and primate embryos. Integrated analysis of mutant transcriptomes revealed funneling of multiple gene activities into discrete regulatory modules. Finally, we delineate how intersections with signaling pathways direct this pivotal mammalian cell state transition. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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