Dynamics of oscillatory phenotypes in Saccharomyces cerevisiae reveal a network of genome‐wide transcriptional oscillators

Abstract

Genetic and environmental factors are well-studied influences on phenotype; however, time is a variable that is rarely considered when studying changes in cellular phenotype. Time-resolved microarray data revealed genome-wide transcriptional oscillation in a yeast continuous culture system with ~2 and ~4 h periods. We mapped the global patterns of transcriptional oscillations into a 3D map to represent different cellular phenotypes of redox cycles. This map shows the dynamic nature of gene expression in that transcripts are ordered and coupled to each other through time and concentration space. Although cells differed in oscillation periods, transcripts involved in certain processes were conserved in a deterministic way. When oscillation period lengthened, the peak to trough ratio of transcripts increased and the fraction of cells in the unbudded (G0/G1) phase of the cell division cycle increased. Decreasing the glucose level in the culture media was one way to increase the redox cycle, possibly from changes in metabolic flux. The period may be responding to lower glucose levels by increasing the fraction of cells in G1 and reducing S-phase gating so that cells can spend more time in catabolic processes. Our results support that gene transcripts are coordinated with metabolic functions and the cell division cycle.

Free Energy Rhythms in Saccharomyces cerevisiae: A Dynamic Perspective with Implications for Ribosomal Biogenesis

“…Fermentor culture conditions for CEN.PK113-7D oscillating with a 4 h period have been previously described (15). The cell concentration was determined using a Coulter counter (Beckman Coulter, Miami, FL).…”

“…The periods of the transcriptional oscillations can be influenced by growth conditions, such as glucose availability, the amount of dissolved oxygen (DO) and by drug treatment (10–14). Time resolved microarray data have demonstrated that the levels of certain transcripts correlate with each other during different phases of the cell cycle (3, 6, 15). Taken together, these studies support a possible correlation between gene transcription and metabolic function (16), as well as a link between transcriptional dynamics and energy requirements and energy release.…”

“…The state of the yeast cell in a culture is constantly changing for example with varying oxygen levels in the culture medium (4, 15). These cells are thought to self-synchronize through cell signaling of small molecules such as hydrogen sulfide and acetaldehyde (8,9).…”

“…The coordination of DO oscillations with timing of DNA replication, mRNA expression, and metabolites has been reported (3, 6, 7, 14). Cells are thought to be less prone to genetic mutations when DNA replication occurs during the reductive phase of the cycle (3, 7, 14, 15). Specifically we used the data reported for two different strains in (3) and (15) respectively to relate transcription levels to work requirements.…”

“…The special feature of the experiments is that many time points were measured, and this allows us to identify cycles in energy requirements and energy consumption. See also the data analysis in (15) and (17, 18). We used three steps to elucidate the changes in the free energy: ( i ) relating the thermodynamic notion of free energy to the level of expression of the transcripts, ( ii ) computing the actual energy changes of the transcription system during the cell cycle by using experimental microarray data, and ( iii ) offering a biological interpretation of the observed dominant energy requirements.…”