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Impact of eIF2α phosphorylation on the translational landscape of mouse embryonic stem cells [Ribo-Seq]

ABSTRACT: The integrated stress response (ISR) is critical for cell survival under stress. In response to diverse environmental cues, eIF2αbecomes phosphorylated, engendering a dramatic change in mRNA translation. The activation of ISR plays a pivotal role in the early embryogenesis but the eIF2-dependent translational landscape in pluripotent embryonic stem cells (ESC) is largely unexplored. We employ a multi-omics approachconsisting of ribosome profiling, proteomics, and metabolomics inwild-type(eIF2α+/+)andphosphorylation-deficient mutant eIF2α(eIF2αA/A)mouse ESCs (mESCs) to investigate phosphorylated (p)-eIF2α-dependent translational control of naïve pluripotency. We show a transient increase in p-eIF2α in the naïve epiblast layer of E4.5 embryos. Absence of eIF2α phosphorylation engenders an exit from naive pluripotency following 2i (two chemical inhibitors of MEK1/2 and GSK3α/β) withdrawal. p-eIF2α controls translation of mRNAs encoding proteins which govern pluripotency, chromatin organization, and glutathione synthesis.Thus, p-eIF2αacts as a key regulator of the naïve pluripotency gene regulatory network.

ORGANISM(S): Mus musculus

PROVIDER: GSE248724 | GEO | 2023/12/29

REPOSITORIES: GEO

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Impact of eIF2α phosphorylation on the translational landscape of mouse embryonic stem cells [RNA-Seq]

Project description:The integrated stress response (ISR) is critical for cell survival under stress. In response to diverse environmental cues, eIF2αbecomes phosphorylated, engendering a dramatic change in mRNA translation. The activation of ISR plays a pivotal role in the early embryogenesis but the eIF2-dependent translational landscape in pluripotent embryonic stem cells (ESC) is largely unexplored. We employ a multi-omics approachconsisting of ribosome profiling, proteomics, and metabolomics inwild-type(eIF2α+/+)andphosphorylation-deficient mutant eIF2α(eIF2αA/A)mouse ESCs (mESCs) to investigate phosphorylated (p)-eIF2α-dependent translational control of naïve pluripotency. We show a transient increase in p-eIF2α in the naïve epiblast layer of E4.5 embryos. Absence of eIF2α phosphorylation engenders an exit from naive pluripotency following 2i (two chemical inhibitors of MEK1/2 and GSK3α/β) withdrawal. p-eIF2α controls translation of mRNAs encoding proteins which govern pluripotency, chromatin organization, and glutathione synthesis.Thus, p-eIF2αacts as a key regulator of the naïve pluripotency gene regulatory network.

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Cue-induced modulation of eIF2α-eIF2Bε underlies axonal translation up-regulation in neural wiring

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eIF4F complex dynamics are important for the activation of the integrated stress response

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