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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 metabolismdependent
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.
