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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

1
Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
2
The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom.
3
Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
4
European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, United Kingdom.
5
Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin, Germany.
6
Department of Molecular Systems Biology, Eidgenoessische Technische Hochschule, Zurich, Switzerland.
7
European Molecular Biology Laboratory, EMBL, Heidelberg, Germany.
#
Contributed equally

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.

PMID:
27572163
PMCID:
PMC5131842
DOI:
10.1038/nmicrobiol.2015.30
[Indexed for MEDLINE]
Free PMC Article

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