Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae

NPJ Syst Biol Appl. 2019 Oct 3:5:35. doi: 10.1038/s41540-019-0112-5. eCollection 2019.

Abstract

Eukaryotic genetic interaction networks (GINs) are extensively described in the Saccharomyces cerevisiae S288C model using deletion libraries, yet being limited to this one genetic background, not informative to individual drug response. Here we created deletion libraries in three additional genetic backgrounds. Statin response was probed with five queries against four genetic backgrounds. The 20 resultant GINs representing drug-gene and gene-gene interactions were not conserved by functional enrichment, hierarchical clustering, and topology-based community partitioning. An unfolded protein response (UPR) community exhibited genetic background variation including different betweenness genes that were network bottlenecks, and we experimentally validated this UPR community via measurements of the UPR that were differentially activated and regulated in statin-resistant strains relative to the statin-sensitive S288C background. These network analyses by topology and function provide insight into the complexity of drug response influenced by genetic background.

Keywords: Biochemical networks; Epistasis; Screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Pharmacological
  • Cluster Analysis
  • Drug Resistance / genetics
  • Drug Resistance / physiology
  • Epistasis, Genetic / genetics
  • Gene Expression Regulation, Fungal / drug effects
  • Gene Expression Regulation, Fungal / genetics
  • Gene Regulatory Networks / genetics*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Models, Genetic
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae Proteins / genetics
  • Unfolded Protein Response / genetics
  • Unfolded Protein Response / physiology

Substances

  • Biomarkers, Pharmacological
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Saccharomyces cerevisiae Proteins