Unraveling condition-dependent networks of transcription factors that control metabolic pathway activity in yeast.
Which transcription factors control the distribution of metabolic fluxes under a given condition? We address this question by systematically quantifying metabolic fluxes in 119 transcription factor deletion mutants of Saccharomyces cerevisiae under five growth conditions. While most knockouts did not affect fluxes, we identified 42 condition-dependent interactions that were mediated by a total of 23 transcription factors that control almost exclusively the cellular decision between respiration and fermentation. This relatively sparse, condition-specific network of active metabolic control contrasts with the much larger gene regulation network inferred from expression and DNA binding data. Based on protein and transcript analyses in key mutants, we identified three enzymes in the tricarboxylic acid cycle as the key targets of this transcriptional control. For the transcription factor Gcn4, we demonstrate that this control is mediated through the PKA and Snf1 signaling cascade. The discrepancy between flux response predictions, based on the known regulatory network architecture and our functional (13)C-data, demonstrates the importance of identifying and quantifying the extent to which regulatory effectors alter cellular functions.
Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
Sarah-Maria
SM
Fendt
Ana Paula
AP
Oliveira
Stefan
S
Christen
Paola
P
Picotti
Reinhard Christoph
RC
Dechant
Uwe
U
Sauer
D002952:Citric Acid Cycle / Q000235:genetics; D004777:Environment; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks / Q000502:physiology*; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D046228:Microarray Analysis; D008954:Models, Biological; D008957:Models, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D054928:Validation Studies as Topic; D015003:Yeasts / Q000235:genetics* / Q000378:metabolism*
D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors