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Nat Microbiol. 2016 Feb 1;1:15030. doi: 10.1038/nmicrobiol.2015.30.

The metabolic background is a global player in Saccharomyces gene expression epistasis.

Author information

Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom.
Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, United Kingdom.
Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin, Germany.
Department of Molecular Systems Biology, Eidgenoessische Technische Hochschule, Zurich, Switzerland.
European Molecular Biology Laboratory, EMBL, Heidelberg, Germany.
Contributed equally


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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