title: The metabolic background is a global player in Saccharomyces gene expression epistasis.
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.
authors: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
authors: Mohammad Tauqeer
authors: MT
authors: Alam
authors: 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.
authors: Aleksej
authors: A
authors: Zelezniak
authors: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
authors: Michael
authors: M
authors: Mülleder
authors: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.|Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
authors: Pavel
authors: P
authors: Shliaha
authors: European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, United Kingdom.
authors: Roland
authors: R
authors: Schwarz
authors: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
authors: Floriana
authors: F
authors: Capuano
authors: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
authors: Jakob
authors: J
authors: Vowinckel
authors: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
authors: Elahe
authors: E
authors: Radmanesfahar
authors: Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin, Germany.
authors: Antje
authors: A
authors: Krüger
authors: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
authors: Enrica
authors: E
authors: Calvani
authors: Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin, Germany.
authors: Steve
authors: S
authors: Michel
authors: Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin, Germany.
authors: Stefan
authors: S
authors: Börno
authors: Department of Molecular Systems Biology, Eidgenoessische Technische Hochschule, Zurich, Switzerland.
authors: Stefan
authors: S
authors: Christen
authors: European Molecular Biology Laboratory, EMBL, Heidelberg, Germany.
authors: Kiran Raosaheb
authors: KR
authors: Patil
authors: Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin, Germany.
authors: Bernd
authors: B
authors: Timmermann
authors: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.|Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd, Cambridge, United Kingdom.
authors: Kathryn S
authors: KS
authors: Lilley
authors: 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.
authors: Markus
authors: M
authors: Ralser
mesh_terms: D004843:Epistasis, Genetic; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D008660:Metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*