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Impact of eIF2α phosphorylation on the translational landscape of mouse embryonic stem cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE248729 | 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.

2023-12-29 | GSE248725 | GEO

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

2023-12-29 | GSE248724 | GEO

Impact of eIF2α phosphorylation on the translational landscape of mouse embryonic stem cells

Project description:Impact of eIF2α phosphorylation on the translational landscape of mouse embryonic stem cells

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

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

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

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

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Decoupling the impact of microRNAs on translational repression versus RNA degradation in embryonic stem cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-07-25 | GSE112767 | GEO

Dynamical modeling of the H3K27 epigenetic landscape in mouse embryonic stem cells.

Project description:The Polycomb system via the methylation of the lysine 27 of histone H3 (H3K27) plays central roles in the silencing of many lineage-specific genes during development. Recent experimental evidence suggested that the recruitment of histone modifying enzymes like the Polycomb repressive complex 2 (PRC2) at specific sites and their spreading capacities from these sites are key to the establishment and maintenance of a proper epigenomic landscape around Polycomb-target genes. Here, to test whether such mechanisms, as a minimal set of qualitative rules, are quantitatively compatible with data, we developed a mathematical model that can predict the locus-specific distributions of H3K27 modifications based on previous biochemical knowledge. Within the biological context of mouse embryonic stem cells, our model showed quantitative agreement with experimental profiles of H3K27 acetylation and methylation around Polycomb-target genes in wild-type and mutants. In particular, we demonstrated the key role of the reader-writer module of PRC2 and of the competition between the binding of activating and repressing enzymes in shaping the H3K27 landscape around transcriptional start sites. The predicted dynamics of establishment and maintenance of the repressive trimethylated H3K27 state suggest a slow accumulation, in perfect agreement with experiments. Our approach represents a first step towards a quantitative description of PcG regulation in various cellular contexts and provides a generic framework to better characterize epigenetic regulation in normal or disease situations.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Cross Talk between eIF2α and eEF2 Phosphorylation Pathways Optimizes Translational Arrest in Response to Oxidative Stress.

Project description:The cellular stress response triggers a cascade of events leading to transcriptional reprogramming and a transient inhibition of global protein synthesis, which is thought to be mediated by phosphorylation of eukaryotic initiation factor-2α (eIF2α). Using mouse embryonic fibroblasts (MEFs) and the fission yeast S. pombe, we report that rapid translational arrest and cell survival in response to hydrogen peroxide-induced oxidative stress do not rely on eIF2α kinases and eIF2α phosphorylation. Rather, H2O2 induces a block in elongation through phosphorylation of eukaryotic elongation factor 2 (eEF2). Kinetic and dose-response analyses uncovered cross talk between the eIF2α and eEF2 phosphorylation pathways, indicating that, in MEFs, eEF2 phosphorylation initiates the acute shutdown in translation, which is maintained by eIF2α phosphorylation. Our results challenge the common conception that eIF2α phosphorylation is the primary trigger of translational arrest in response to oxidative stress and point to integrated control that may facilitate the survival of cancer cells.

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Landscape of monoallelic DNA accessibility in mouse embryonic stem cells and neural progenitor cells.

Project description:We developed an allele-specific assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to genotype and profile active regulatory DNA across the genome. Using a mouse hybrid F1 system, we found that monoallelic DNA accessibility across autosomes was pervasive, developmentally programmed and composed of several patterns. Genetically determined accessibility was enriched at distal enhancers, but random monoallelically accessible (RAMA) elements were enriched at promoters and may act as gatekeepers of monoallelic mRNA expression. Allelic choice at RAMA elements was stable across cell generations and bookmarked through mitosis. RAMA elements in neural progenitor cells were biallelically accessible in embryonic stem cells but premarked with bivalent histone modifications; one allele was silenced during differentiation. Quantitative analysis indicated that allelic choice at the majority of RAMA elements is consistent with a stochastic process; however, up to 30% of RAMA elements may deviate from the expected pattern, suggesting a regulated or counting mechanism.

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