Mapping Condition-Dependent Regulation of Lipid Metabolism inSaccharomyces cerevisiae

Abstract

Lipids play a central role in cellular function as constituents of membranes, as signaling molecules, and as storage materials. Although much is known about the role of lipids in regulating specific steps of metabolism, comprehensive studies integrating genome-wide expression data, metabolite levels, and lipid levels are currently lacking. Here, we map condition-dependent regulation controlling lipid metabolism in Saccharomyces cerevisiae by measuring 5636 mRNAs, 50 metabolites, 97 lipids, and 57 13C-reaction fluxes in yeast using a three-factor full-factorial design. Correlation analysis across eight environmental conditions revealed 2279 gene expression level-metabolite/lipid relationships that characterize the extent of transcriptional regulation in lipid metabolism relative to major metabolic hubs within the cell. To query this network, we developed integrative methods for correlation of multi-omics datasets that elucidate global regulatory signatures. Our data highlight many characterized regulators of lipid metabolism and reveal that sterols are regulated more at the transcriptional level than are amino acids. Beyond providing insights into the systems-level organization of lipid metabolism, we anticipate that our dataset and approach can join an emerging number of studies to be widely used for interrogating cellular systems through the combination of mathematical modeling and experimental biology.

Mapping condition-dependent regulation of metabolism in yeast through genome-scale modeling

“…Experimental measurements for the specific growth rate, specific substrate consumption rate and specific product formation rate in chemostat cultures under four different conditions were taken from our previous study [20] and compared to simulated data using FBA (for more information, see materials and methods and Additional file 5). The four conditions that were considered were carbon limited aerobic growth, nitrogen limited aerobic growth, carbon limited anaerobic growth and nitrogen limited anaerobic growth.…”

“…Chemostat cultivations were performed at a dilution rate of 0.05 h -1 under the same four different conditions as used for simulations above (carbon limited, nitrogen limited, aerobic and anaerobic) and microarray data as well as external and intracellular flux measurements was obtained for each condition [20]. We were particularly interested in changes that occur both on the transcript level and on the flux level, i.e.…”

“…Experimental data were collected from literature for chemostat cultivations performed at various dilution rates under each of the four different conditions: carbon limited aerobic [20,32-35], carbon limited anaerobic [36,37], nitrogen limited aerobic [35,36,38,39] and nitrogen limited anaerobic [40,41] (Additional file 5). For simulation purposes the uptake of glucose, NH 3 and oxygen were constrained in the model according to the measured values for each experiment.…”

“…Experimental data from chemostat cultivations from four different conditions (carbon limited, nitrogen limited, aerobic and anaerobic) was taken from Jewett et al [20]. The raw transcriptome data were normalized using the Probe Logarithmic Intensity Error (PLIER) method and the moderated t-statistic was used to identify significantly changed genes between two conditions.…”

Genome scale models of yeast: towards standardized evaluation and consistent omic integration

“…The most typical approach is to use extracellular measurements (generally under chemostat conditions) to infer exchange fluxes used for FBA simulation, either as sole data 20,145,146 and as input in kinetic modeling [113][114][115]133,134 and other of the already reviewed methods 80,94,107,108,110,111,132,144 . The most typical approach is to use extracellular measurements (generally under chemostat conditions) to infer exchange fluxes used for FBA simulation, either as sole data 20,145,146 and as input in kinetic modeling [113][114][115]133,134 and other of the already reviewed methods 80,94,107,108,110,111,132,144 .…”