Abstract
BackgroundCharacterization of cellular growth is central to understanding living systems. Here, we applied a three-factor design to study the relationship between specific growth rate and genome-wide gene expression in 36 steady-state chemostat cultures of Saccharomyces cerevisiae. The three factors we considered were specific growth rate, nutrient limitation, and oxygen availability.ResultsWe identified 268 growth rate dependent genes, independent of nutrient limitation and oxygen availability. The transcriptional response was used to identify key areas in metabolism around which mRNA expression changes are significantly associated. Among key metabolic pathways, this analysis revealed de novo synthesis of pyrimidine ribonucleotides and ATP producing and consuming reactions at fast cellular growth. By scoring the significance of overlap between growth rate dependent genes and known transcription factor target sets, transcription factors that coordinate balanced growth were also identified. Our analysis shows that Fhl1, Rap1, and Sfp1, regulating protein biosynthesis, have significantly enriched target sets for genes up-regulated with increasing growth rate. Cell cycle regulators, such as Ace2 and Swi6, and stress response regulators, such as Yap1, were also shown to have significantly enriched target sets.ConclusionOur work, which is the first genome-wide gene expression study to investigate specific growth rate and consider the impact of oxygen availability, provides a more conservative estimate of growth rate dependent genes than previously reported. We also provide a global view of how a small set of transcription factors, 13 in total, contribute to control of cellular growth rate. We anticipate that multi-factorial designs will play an increasing role in elucidating cellular regulation.
Highlights
Characterization of cellular growth is central to understanding living systems
URA5 is not regulated by pathway intermediates and our analysis suggests that transcriptional control of this critical enzyme involved in DNA synthesis helps to mobilize resources necessary for growth
Comparison with previous growth rate studies Compared with earlier studies on the influence of the specific growth rate on global transcription, our analysis provides a much more moderate estimate of the number of growth rate dependent genes
Summary
We applied a three-factor design to study the relationship between specific growth rate and genome-wide gene expression in 36 steady-state chemostat cultures of Saccharomyces cerevisiae. The three factors we considered were specific growth rate, nutrient limitation, and oxygen availability. A number of previous studies in S. cerevisiae have focused on the genome-wide transcriptional response of cells to nutrient limitation [3,4,5], oxygen availability [6,7,8] and growth rate (Table 1). The specific growth rate of the culture (h-1) must be controlled. The general approach for obtaining constant specific growth rate is through continuous i.e. chemostat cultivation. The specific growth rate is kept constant by continuously feeding a culture with fresh nutrients having one limiting reagent at a specific dilution rate (D). By studying factors in addition to specific growth rate (e.g. nutrient limitation), growth rate dependent genes that are independent of environmental factors can be identified
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