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Stochastic scanning events on the GCN4 mRNA 5’ untranslated region generate cell-to-cell heterogeneity in the yeast nutritional stress response
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Meng, Xiang, Reed, Alan Pledger, Lai, Sandie, Szavits-Nossan, Juraj and McCarthy, John E. G. (2023) Stochastic scanning events on the GCN4 mRNA 5’ untranslated region generate cell-to-cell heterogeneity in the yeast nutritional stress response. Nucleic Acids Research, 51 (13). pp. 6609-6621. doi:10.1093/nar/gkad433 ISSN 0305-1048.
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Official URL: http://doi.org/10.1093/nar/gkad433
Abstract
Gene expression stochasticity is inherent in the functional properties and evolution of biological systems, creating non-genetic cellular individuality and influencing multiple processes, including differentiation and stress responses. In a distinct form of non-transcriptional noise, we find that interactions of the yeast translation machinery with the GCN4 mRNA 5’UTR, which underpins starvation-induced regulation of this transcriptional activator gene, manifest stochastic variation across cellular populations. We use flow cytometry, fluorescence-activated cell sorting and microfluidics coupled to fluorescence microscopy to characterize the cell-to-cell heterogeneity of GCN4-5’UTR-mediated translation initiation. GCN4-5’UTR-mediated translation is generally not de-repressed under non-starvation conditions; however, a sub-population of cells consistently manifests a stochastically enhanced GCN4 translation (SETGCN4) state that depends on the integrity of the GCN4 uORFs. This sub-population is eliminated upon deletion of the Gcn2 kinase that phosphorylates eIF2α under nutrient-limitation conditions, or upon mutation to Ala of the Gcn2 kinase target site, eIF2α-Ser51. SETGCN4 cells isolated using cell sorting spontaneously regenerate the full bimodal population distribution upon further growth. Analysis of ADE8::ymRuby3/ GCN4::yEGFP cells reveals enhanced Gcn4-activated biosynthetic pathway activity in SETGCN4 cells under non-starvation conditions. Computational modeling interprets our experimental observations in terms of a novel translational noise mechanism underpinned by natural variations in Gcn2 kinase activity.
Item Type: | Journal Article | |||||||||||||||||||||
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Subjects: | Q Science > QH Natural history > QH426 Genetics Q Science > QK Botany Q Science > QR Microbiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | |||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Gene expression, Genetic regulation, Saccharomyces cerevisiae -- Effect of of stress on, Yeast fungi -- Effect of stress on | |||||||||||||||||||||
Journal or Publication Title: | Nucleic Acids Research | |||||||||||||||||||||
Publisher: | Oxford University Press | |||||||||||||||||||||
ISSN: | 0305-1048 | |||||||||||||||||||||
Official Date: | July 2023 | |||||||||||||||||||||
Dates: |
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Volume: | 51 | |||||||||||||||||||||
Number: | 13 | |||||||||||||||||||||
Page Range: | pp. 6609-6621 | |||||||||||||||||||||
DOI: | 10.1093/nar/gkad433 | |||||||||||||||||||||
Status: | Peer Reviewed | |||||||||||||||||||||
Publication Status: | Published | |||||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||||||||
Date of first compliant deposit: | 5 June 2023 | |||||||||||||||||||||
Date of first compliant Open Access: | 5 June 2023 | |||||||||||||||||||||
RIOXX Funder/Project Grant: |
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