Dynamic patterns of gene expression match extracellular signals through push-pull regulation

Cells can match gene expression to a range of a particular signal. For example, budding yeast expresses at least seven hexose-transporter (HXT) genes in different concentration ranges of extracellular glucose. Using time-lapse microscopy, microfluidics, dynamic glucose inputs, and mathematical modelling, we determine how this glucose matching of HXT expression occurs mechanistically. The glucose-sensing network generates a push-pull regulation using two pairs of regulators: rising glucose weakens, or “pulls”, repression via regulators Mth1 and Std1 while simultaneously strengthening, or “pushing”, repression via regulators Mig1 and Mig2; falling glucose reverses this push-pull. The regulators’ combined activity reports extracellular glucose. Cells match HXT expression to glucose because HXT promoters couple to the regulators in ways specific to low, medium, or high-affinity transporters. By rewiring transcription and using model-predicted perturbations, we demonstrate how an HXT encoding a medium-affinity transporter can respond as one encoding either a low- or a high-affinity transporter. Matching gene expression to a pattern of input is fundamental; we believe push-pull regulation to be widespread.