부산대학교 도서관

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. SYNOPSIS: Combining a haploid transposon‐based screen and systems biology, this resource work identifies gene networks controlling the exit of mouse embryonic stem cells (ESC) from naïve pluripotency, and delineates signalling intersections involved. Transcriptional characterization of 73 differentiation‐defective ESC lines defines discrete gene modules and signalling inputs essential for the exit from naïve pluripotency.Genetic depletion of specific exit genes in ESCs results in increased molecular similarity to the pre‐implantation epiblast in utero.Identification of 496 naïve state‐associated genes establishes an extended naïve pluripotency network conserved in primate embryos.The transcription factor Klf2 is only weakly wired into the mouse naïve pluripotency network. [ABSTRACT FROM AUTHOR]