A pharmaco-epistasis strategy reveals a new cell size controlling pathway in yeast.
Cell size is a complex quantitative trait resulting from interactions between intricate genetic networks and environmental conditions. Here, taking advantage of previous studies that uncovered hundreds of genes affecting budding yeast cell size homeostasis, we performed a wide pharmaco-epistasis analysis using drugs mimicking cell size mutations. Simple epistasis relationship emerging from this approach allowed us to characterize a new cell size homeostasis pathway comprising the sirtuin Sir2, downstream effectors including the large ribosomal subunit (60S) and the transcriptional regulators Swi4 and Swi6. We showed that this Sir2/60S signaling route acts independently of other previously described cell size controlling pathways and may integrate the metabolic status of the cell through NAD(+) intracellular concentration. Finally, although Sir2 and the 60S subunits regulate both cell size and replicative aging, we found that there is no clear causal relationship between these two complex traits. This study sheds light on a pathway of >50 genes and illustrates how pharmaco-epistasis applied to yeast offers a potent experimental framework to explore complex genotype/phenotype relationships.
1] Université Bordeaux, IBGC, UMR 5095, Bordeaux, France [2] Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Bordeaux, France.
Fabien
F
Moretto
Isabelle
I
Sagot
Bertrand
B
Daignan-Fornier
Benoît
B
Pinson
D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D015966:Gene Expression Regulation, Fungal; D005838:Genotype; D006706:Homeostasis; D008957:Models, Genetic; D009154:Mutation; D009243:NAD / Q000378:metabolism; D010641:Phenotype; D040641:Quantitative Trait Loci; D054683:Ribosome Subunits, Large, Eukaryotic / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; C062214:SWI4 protein, S cerevisiae; C075111:SWI6 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D014157:Transcription Factors; D009243:NAD; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2