Transcriptional noise is known to be an important cause of cellular heterogeneity and phenotypic variation. The extent to which molecular interaction networks may have evolved to either filter or exploit transcriptional noise is a much debated question. The yeast genetic network regulating galactose metabolism involves two proteins, Gal3p and Gal80p, that feed back positively and negatively, respectively, on GAL gene expression. Using kinetic modeling and experimental validation, we demonstrate that these feedback interactions together are important for (i) controlling the cell-to-cell variability of GAL gene expression and (ii) ensuring that cells rapidly switch to an induced state for galactose uptake.
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We thank D. Hwang for helpful advice on the statistical analysis, H. Kostner for assistance with the QPCR experiments and E. Schweighofer for assistance with the cluster computing infrastructure. This work was supported in part by grants from the US National Institutes of Health (GM076547, GM067228).
The authors declare no competing financial interests.
Control experiments. (PDF 70 kb)
Analytic model of galactose import. (PDF 25 kb)
Simulated distribution of the number of molecules of Gal80p homodimer within the nucleus, for a cell population of wild-type and mutant strains grown on raffinose (noninducing media). (PDF 42 kb)
Steady-state galactose dose-response. (PDF 63 kb)
Simulated growth of wild-type and mutant strains on alternating galactose and raffinose media. (PDF 55 kb)
Fractional activity level of the reporter at 6 h, for the wild-type and mutant strains on different initial concentrations of galactose. (PDF 10 kb)
Oligonucleotide primers used in strain construction and in QPCR measurement of GAL3 and GAL80 expression levels. (PDF 18 kb)
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Ramsey, S., Smith, J., Orrell, D. et al. Dual feedback loops in the GAL regulon suppress cellular heterogeneity in yeast. Nat Genet 38, 1082–1087 (2006). https://doi.org/10.1038/ng1869
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