Cellular Noise Regulons Underlie Fluctuations in Saccharomyces cerevisiae

Stochasticity is a hallmark of cellular processes, and different classes of genes show large differences in their cell-to-cell variability (noise). To decipher the sources and consequences of this noise, we systematically measured pairwise correlations between large numbers of genes, including those with high variability. We find that there is substantial pathway variability shared across similarly regulated genes. This induces quantitative correlations in the expression of functionally related genes such as those involved in the Msn2/4 stress response pathway, amino-acid biosynthesis, and mitochondrial maintenance. Bioinformatic analyses and genetic perturbations suggest that fluctuations in PKA and Tor signaling contribute to pathway-specific variability. Our results argue that a limited number of well-delineated noise regulons operate across a yeast cell and that such coordinated fluctuations enable a stochastic but coherent induction of functionally related genes. Finally, we show that pathway noise is a quantitative tool for exploring pathway features and regulatory relationships in un-stimulated systems.