Letter | Published:

Dual feedback loops in the GAL regulon suppress cellular heterogeneity in yeast

Nature Genetics volume 38, pages 10821087 (2006) | Download Citation

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Abstract

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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Acknowledgements

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).

Author information

Affiliations

  1. Institute for Systems Biology, 1441 N 34th Street, Seattle, Washington 98103, USA.

    • Stephen A Ramsey
    • , Jennifer J Smith
    • , David Orrell
    • , Marcello Marelli
    • , Timothy W Petersen
    • , Pedro de Atauri
    • , Hamid Bolouri
    •  & John D Aitchison

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Contributions

S.A.R., J.J.S., D.O., H.B. and J.D.A. designed the study. J.J.S., M.M. and T.W.P. carried out the experimental validation. S.A.R., D.O. and P.A. performed the modeling and simulations. S.A.R., J.J.S., H.B. and J.D.A. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Hamid Bolouri or John D Aitchison.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Control experiments.

  2. 2.

    Supplementary Fig. 2

    Analytic model of galactose import.

  3. 3.

    Supplementary Fig. 3

    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).

  4. 4.

    Supplementary Fig. 4

    Steady-state galactose dose-response.

  5. 5.

    Supplementary Fig. 5

    Simulated growth of wild-type and mutant strains on alternating galactose and raffinose media.

  6. 6.

    Supplementary Table 1

    Fractional activity level of the reporter at 6 h, for the wild-type and mutant strains on different initial concentrations of galactose.

  7. 7.

    Supplementary Table 2

    Oligonucleotide primers used in strain construction and in QPCR measurement of GAL3 and GAL80 expression levels.

  8. 8.

    Supplementary Note

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DOI

https://doi.org/10.1038/ng1869

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