Predicting Cellular Growth from Gene Expression Signatures
Figure 8
Perturbations and potential transcriptional regulators of the growth rate response.
(A) Predicted growth rates for gal1Δ cells shifted to glucose, to galactose, and to galactose with a constitutively active RAS2G19V allele. On glucose, rapid growth is induced within ∼40 m; growth on galactose falls to low levels within ∼40 m, as it cannot be metabolized by this mutant. However, when glucose sensing is emulated by artificial activation of the Ras/PKA pathway, the transcriptional regulatory network attempts to induce rapid growth within ∼60–80 m despite the unavailability of appropriate nutrients. This disconnect between actual and perceived cellular state leads to cell death within 4–6 hours and suggests that nutrient sensing (as opposed to metabolic activity or internal cellular state) is responsible for a large portion of the transcriptional growth rate response. (B) Regulatory binding sites enriched in growth up- and down-regulated genes. We clustered the yeast genome by degree of growth rate response, yielding ten clusters with average responses ranging from −12.0 (strongly downregulated with increasing growth rate) to 8.6 (strongly upregulated). The FIRE program [34] predicted 10 regulatory motifs in the upstream flanks and 3′ UTRs of the most up- and down-regulated clusters. These included the known stress-responsive MSN2/4 binding sites in downregulated genes, the ribosomal regulators RAP1 and PUF4 in upregulated genes, and INO4 sites in upregulated genes (possibly corresponding to its role in the stress response and fatty acid biosynthesis [35]. We also identified five additional putative growth regulatory sites for which the binding factor is not yet known.