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Title: Single-cell RNA sequencing reveals intrinsic and extrinsic regulatory heterogeneity in yeast responding to stress

Abstract

From bacteria to humans, individual cells within isogenic populations can show significant variation in stress tolerance, but the nature of this heterogeneity is not clear. To investigate this, we used single-cell RNA sequencing to quantify transcript heterogeneity in single Saccharomyces cerevisiae cells treated with and without salt stress to explore population variation and identify cellular covariates that influence the stress-responsive transcriptome. Leveraging the extensive knowledge of yeast transcriptional regulation, we uncovered significant regulatory variation in individual yeast cells, both before and after stress. We also discovered that a subset of cells appears to decouple expression of ribosomal protein genes from the environmental stress response in a manner partly correlated with the cell cycle but unrelated to the yeast ultradian metabolic cycle. Live-cell imaging of cells expressing pairs of fluorescent regulators, including the transcription factor Msn2 with Dot6, Sfp1, or MAP kinase Hog1, revealed both coordinated and decoupled nucleocytoplasmic shuttling. Together with transcriptomic analysis, our results suggest that cells maintain a cellular filter against decoupled bursts of transcription factor activation but mount a stress response upon coordinated regulation, even in a subset of unstressed cells.

Authors:
ORCiD logo [1];  [2];  [1];  [1];  [1];  [1];  [3];  [4];  [4];  [4];  [1];  [5];  [1];  [6]
  1. Univ. of Wisconsin, Madison, WI (United States)
  2. Stanford Univ.,Stanford, CA (United States)
  3. Stanford Univ.,Stanford, CA (United States); Univ. of California San Diego, La Jolla, CA (United States)
  4. USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
  5. Stanford Univ.,Stanford, CA (United States); Chan Zuckerberg Biohub, San Francisco, CA, (United States)
  6. Hebrew Univ. of Jerusalem, Jerusalem (Israel)
Publication Date:
Research Org.:
Univ. of Wisconsin, Madison, WI (United States); Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1499873
Alternate Identifier(s):
OSTI ID: 1619084
Grant/Contract Number:  
FC02-07ER64494; AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Biology (Online)
Additional Journal Information:
Journal Name: PLoS Biology (Online); Journal Volume: 15; Journal Issue: 12; Journal ID: ISSN 1545-7885
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Gasch, Audrey P., Yu, Feiqiao Brian, Hose, James, Escalante, Leah E., Place, Mike, Bacher, Rhonda, Kanbar, Jad, Ciobanu, Doina, Sandor, Laura, Grigoriev, Igor V., Kendziorski, Christina, Quake, Stephen R., McClean, Megan N., and Balaban, Nathalie. Single-cell RNA sequencing reveals intrinsic and extrinsic regulatory heterogeneity in yeast responding to stress. United States: N. p., 2017. Web. doi:10.1371/journal.pbio.2004050.
Gasch, Audrey P., Yu, Feiqiao Brian, Hose, James, Escalante, Leah E., Place, Mike, Bacher, Rhonda, Kanbar, Jad, Ciobanu, Doina, Sandor, Laura, Grigoriev, Igor V., Kendziorski, Christina, Quake, Stephen R., McClean, Megan N., & Balaban, Nathalie. Single-cell RNA sequencing reveals intrinsic and extrinsic regulatory heterogeneity in yeast responding to stress. United States. doi:10.1371/journal.pbio.2004050.
Gasch, Audrey P., Yu, Feiqiao Brian, Hose, James, Escalante, Leah E., Place, Mike, Bacher, Rhonda, Kanbar, Jad, Ciobanu, Doina, Sandor, Laura, Grigoriev, Igor V., Kendziorski, Christina, Quake, Stephen R., McClean, Megan N., and Balaban, Nathalie. Thu . "Single-cell RNA sequencing reveals intrinsic and extrinsic regulatory heterogeneity in yeast responding to stress". United States. doi:10.1371/journal.pbio.2004050. https://www.osti.gov/servlets/purl/1499873.
@article{osti_1499873,
title = {Single-cell RNA sequencing reveals intrinsic and extrinsic regulatory heterogeneity in yeast responding to stress},
author = {Gasch, Audrey P. and Yu, Feiqiao Brian and Hose, James and Escalante, Leah E. and Place, Mike and Bacher, Rhonda and Kanbar, Jad and Ciobanu, Doina and Sandor, Laura and Grigoriev, Igor V. and Kendziorski, Christina and Quake, Stephen R. and McClean, Megan N. and Balaban, Nathalie},
abstractNote = {From bacteria to humans, individual cells within isogenic populations can show significant variation in stress tolerance, but the nature of this heterogeneity is not clear. To investigate this, we used single-cell RNA sequencing to quantify transcript heterogeneity in single Saccharomyces cerevisiae cells treated with and without salt stress to explore population variation and identify cellular covariates that influence the stress-responsive transcriptome. Leveraging the extensive knowledge of yeast transcriptional regulation, we uncovered significant regulatory variation in individual yeast cells, both before and after stress. We also discovered that a subset of cells appears to decouple expression of ribosomal protein genes from the environmental stress response in a manner partly correlated with the cell cycle but unrelated to the yeast ultradian metabolic cycle. Live-cell imaging of cells expressing pairs of fluorescent regulators, including the transcription factor Msn2 with Dot6, Sfp1, or MAP kinase Hog1, revealed both coordinated and decoupled nucleocytoplasmic shuttling. Together with transcriptomic analysis, our results suggest that cells maintain a cellular filter against decoupled bursts of transcription factor activation but mount a stress response upon coordinated regulation, even in a subset of unstressed cells.},
doi = {10.1371/journal.pbio.2004050},
journal = {PLoS Biology (Online)},
number = 12,
volume = 15,
place = {United States},
year = {2017},
month = {12}
}

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    • Proceedings of the National Academy of Sciences, Vol. 115, Issue 23
    • DOI: 10.1073/pnas.1716659115

    Single-Cell RNA Sequencing of Plant-Associated Bacterial Communities
    journal, October 2019

    • Ma, Qin; Bücking, Heike; Gonzalez Hernandez, Jose L.
    • Frontiers in Microbiology, Vol. 10
    • DOI: 10.3389/fmicb.2019.02452

    Single-Cell RNA Sequencing of Plant-Associated Bacterial Communities
    journal, October 2019

    • Ma, Qin; Bücking, Heike; Gonzalez Hernandez, Jose L.
    • Frontiers in Microbiology, Vol. 10
    • DOI: 10.3389/fmicb.2019.02452

    Single-Cell RNA Sequencing-Based Computational Analysis to Describe Disease Heterogeneity
    journal, July 2019


    Distributed and dynamic intracellular organization of extracellular information
    journal, May 2018

    • Granados, Alejandro A.; Pietsch, Julian M. J.; Cepeda-Humerez, Sarah A.
    • Proceedings of the National Academy of Sciences, Vol. 115, Issue 23
    • DOI: 10.1073/pnas.1716659115

    Extrinsic Noise and Heavy-Tailed Laws in Gene Expression
    journal, March 2020


    Single-cell imaging and RNA sequencing reveal patterns of gene expression heterogeneity during fission yeast growth and adaptation
    journal, February 2019


    Sensitive high-throughput single-cell RNA-seq reveals within-clonal transcript correlations in yeast populations
    journal, February 2019


    High throughput gene expression profiling of yeast colonies with microgel-culture Drop-seq
    journal, January 2019

    • Liu, Leqian; Dalal, Chiraj K.; Heineike, Benjamin M.
    • Lab on a Chip, Vol. 19, Issue 10
    • DOI: 10.1039/c9lc00084d

    Complex genetic and epigenetic regulation deviates gene expression from a unifying global transcriptional program
    journal, September 2019


    Control of nongenetic heterogeneity in growth rate and stress tolerance of Saccharomyces cerevisiae by cyclic AMP-regulated transcription factors
    journal, November 2018


    Latent transcriptional variations of individual Plasmodium falciparum uncovered by single-cell RNA-seq and fluorescence imaging
    journal, December 2019


    Widespread inter‐individual gene expression variability in Arabidopsis thaliana
    journal, January 2019

    • Cortijo, Sandra; Aydin, Zeynep; Ahnert, Sebastian
    • Molecular Systems Biology, Vol. 15, Issue 1
    • DOI: 10.15252/msb.20188591