Abstract
The regulation of gene expression in response to nutrient availability is fundamental to the genotype-phenotype relationship. The metabolic-genetic make-up of the cell, as reflected in auxotrophy, is hence likely to be a determinant of gene expression. Here, we address the importance of the metabolic-genetic background by monitoring transcriptome, proteome and metabolome in a repertoire of 16 Saccharomyces cerevisiae laboratory backgrounds, combinatorially perturbed in histidine, leucine, methionine and uracil biosynthesis. The metabolic background affected up to 85% of the coding genome. Suggesting widespread confounding, these transcriptional changes show, on average, 83% overlap between unrelated auxotrophs and 35% with previously published transcriptomes generated for non-metabolic gene knockouts. Background-dependent gene expression correlated with metabolic flux and acted, predominantly through masking or suppression, on 88% of transcriptional interactions epistatically. As a consequence, the deletion of the same metabolic gene in a different background could provoke an entirely different transcriptional response. Propagating to the proteome and scaling up at the metabolome, metabolic background dependencies reveal the prevalence of metabolism-dependent epistasis at all regulatory levels. Urging a fundamental change of the prevailing laboratory practice of using auxotrophs and nutrient supplemented media, these results reveal epistatic intertwining of metabolism with gene expression on the genomic scale.
Highlights
The regulation of gene expression in response to nutrient availability is fundamental to the genotype–phenotype relationship
As HIS3, LEU2, MET15 and URA3 have frequently been exploited as genetic selection markers, these results suggest that metabolic transcriptional signatures could have confounded previous gene expression experiments. mRNA expression data collected for a variety of single gene knockouts in different contexts and laboratories, but all generated in auxotrophic BY4741 backgrounds, were obtained from ArrayExpress[18] and reprocessed to achieve identical cutoff criteria
Metabolic genes are often nicknamed ‘housekeeping’ genes, which incorrectly implies that the metabolism is static in nature
Summary
The regulation of gene expression in response to nutrient availability is fundamental to the genotype–phenotype relationship. Metabolic activity needs to be adapted constantly to match cellular physiology, nutrition, growth rate and stress situations This dual dependency on both cell-extrinsic and -intrinsic properties renders metabolism a key mediator of gene–environment interactions, while its size represents a quantitative factor in physiology and gene expression[8,9,10]. Gene expression is affected in a metabolism-dependent manner, and on 88% of transcriptional events involving 77% of the differentially expressed transcripts we detect evidence for epistatic interactions occurring between metabolic genes These interactions are found to have a fundamental impact on the gene expression response that follows gene deletions, and reveal the metabolic genotype (or metabotype) to be, on a global scale, responsible for context-dependent biological responses on the transcriptome, proteome and metabolome. Metabolic–genetic background differences, dismissively considered to be harmless in pre-genomic times, could have affected the outcome of a large number of experiments
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