Altered expression response upon repeated gene repression in single yeast cells

Schuh, Lea; Kukhtevich, Igor; Bheda, Poonam; Schulz, Melanie; Bordukova, Maria; Schneider, Robert und Marr, Carsten (2022): Altered expression response upon repeated gene repression in single yeast cells.
In: PLOS Computational Biology 18(10), e1010640

Abstract

Cells must continuously adjust to changing environments and, thus, have evolved mechanisms allowing them to respond to repeated stimuli. While faster gene induction upon a repeated stimulus is known as reinduction memory, responses to repeated repression have been less studied so far. Here, we studied gene repression across repeated carbon source shifts in over 1,500 single Saccharomyces cerevisiae cells. By monitoring the expression of a carbon source-responsive gene, galactokinase 1 (Gal1), and fitting a mathematical model to the single-cell data, we observed a faster response upon repeated repressions at the population level. Exploiting our single-cell data and quantitative modeling approach, we discovered that the faster response is mediated by a shortened repression response delay, the estimated time between carbon source shift and Gal1 protein production termination. Interestingly, we can exclude two alternative hypotheses, i) stronger dilution because of e.g., increased proliferation, and ii) a larger fraction of repressing cells upon repeated repressions. Collectively, our study provides a quantitative description of repression kinetics in single cells and allows us to pinpoint potential mechanisms underlying a faster response upon repeated repression. The computational results of our study can serve as the starting point for experimental follow-up studies. Author summary Cells have to continuously adjust to their environment and cope with changing temperature, stress conditions, or metabolic resources. Yeast cells exposed to repeated carbon source shifts have shown to be primed by their first exposure, exhibiting enhanced gene expression of specific genes later on. However, how cells respond to a repeated repressive stimulus, e.g., withdrawal of metabolic resources, has been so far much less studied. For this, we investigated the expression kinetics of a carbon source-responsive gene across repeated repressions. We measured single-cell expression and used mathematical modeling to evaluate potential causes underlying an observed faster repression response upon a repeated stimulus. Specifically, we investigated whether i) an increased dilution due to e.g., proliferation, ii) an increased fraction of repressing cells, or iii) different kinetic parameters in the repeated repression cause the observed faster response in the second repression. Leveraging quantitative mathematical model comparison, we discovered that the faster response is mediated by a shortened estimated time between carbon source shift and protein production termination at the single-cell level. Our study provides a quantitative description of repression kinetics in single cells and allows us to pinpoint potential mechanisms underlying a faster response upon repeated repression.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Biologie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie
• ISSN: 1553-734X
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 213249687
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 325871075