Journal
NATURE MICROBIOLOGY
Volume 1, Issue 3, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/NMICROBIOL.2015.30
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Funding
- Wellcome Trust [RG 093735/Z/10/Z]
- ERC [260809]
- Isaac Newton Trust [RG 68998]
- Darwin Trust of Edinburgh
- European Research Council (ERC) [260809] Funding Source: European Research Council (ERC)
- Wellcome Trust [093735/Z/10/Z] Funding Source: Wellcome Trust
- The Francis Crick Institute [10134] Funding Source: researchfish
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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.
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