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


  • M.T. Alam
  • A. Zelezniak
  • M. Mülleder
  • P. Shliaha
  • R. Schwarz
  • F. Capuano
  • J. Vowinckel
  • E. Radmaneshfar
  • A. Krüger
  • E. Calvani
  • S. Michel
  • S. Börno
  • S. Christen
  • K.R. Patil
  • B. Timmermann
  • K.S. Lilley
  • M. Ralser


  • Nature Microbiology


  • Nat Microbiol 1: 15030


  • 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.