Abstract
Bimodal gene expression by genetically identical cells is a pervasive feature of signaling networks and has been suggested to allow organisms to hedge their 'bets' in uncertain conditions. In the galactose-utilization (GAL) pathway of Saccharomyces cerevisiae, gene induction is unimodal or bimodal depending on natural genetic variation and pre-induction conditions. Here, we find that this variation in modality arises from regulation of two features of the pathway response: the fraction of cells that show induction and their level of expression. GAL3, the galactose sensor, controls the fraction of induced cells, and titrating its expression is sufficient to control modality; moreover, all the observed differences in modality between different pre-induction conditions and among natural isolates can be explained by changes in GAL3's regulation and activity. The ability to switch modality by tuning the activity of a single protein may allow rapid adaptation of bet hedging to maximize fitness in complex environments.
Highlights
Non-genetic heterogeneity is a pervasive feature of gene expression and cellular signaling [1,2,3]
To study what causes the GAL response to be unimodal in some strain backgrounds and bimodal in other 47 strain backgrounds, we measured the expression of a GAL1 promoter driving YFP (GAL1pr-YFP) in 30 48 geographically and ecologically diverse yeast strains [19,20,21] grown in different combinations of glucose 49 and galactose (Figure 1A)
In contrast to our results when titrating galactose 59 in the presence of glucose, all 30 of our natural isolates showed bimodal responses when we titrated the galactose concentration in the absence of glucose (Figure 1D, Figure 1—figure supplement 3)
Summary
Non-genetic heterogeneity is a pervasive feature of gene expression and cellular signaling [1,2,3]. The galactose-utilization (GAL) pathway in Saccharomyces cerevisiae is a well-characterized bimodal response and a classic model of microbial decision-making [8, 9]. Bimodality of GAL gene expression has been attributed to bistability arising from positive feedback through the Gal1p kinase and the Gal3p transducer [10, 11]. Perturbations of many of the components of the GAL pathway such as the Gal2p permease, the Gal4p activator, and the Gal80p repressor have been found to affect quantitative features of the GAL response [11,12,13,14] and in principle could modify the feedback in the system and affect whether the response is bimodal or unimodal. Only changes in Gal1p and Gal3p [10, 11] have been shown to affect modality
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