title: Transcription factor control of growth rate dependent genes in Saccharomyces cerevisiae: a three factor design.
abstract: BACKGROUND
  Characterization of cellular growth is central to understanding living systems. Here, we applied a three-factor design to study the relationship between specific growth rate and genome-wide gene expression in 36 steady-state chemostat cultures of Saccharomyces cerevisiae. The three factors we considered were specific growth rate, nutrient limitation, and oxygen availability.
  
  
  RESULTS
  We identified 268 growth rate dependent genes, independent of nutrient limitation and oxygen availability. The transcriptional response was used to identify key areas in metabolism around which mRNA expression changes are significantly associated. Among key metabolic pathways, this analysis revealed de novo synthesis of pyrimidine ribonucleotides and ATP producing and consuming reactions at fast cellular growth. By scoring the significance of overlap between growth rate dependent genes and known transcription factor target sets, transcription factors that coordinate balanced growth were also identified. Our analysis shows that Fhl1, Rap1, and Sfp1, regulating protein biosynthesis, have significantly enriched target sets for genes up-regulated with increasing growth rate. Cell cycle regulators, such as Ace2 and Swi6, and stress response regulators, such as Yap1, were also shown to have significantly enriched target sets.
  
  
  CONCLUSIONS
  Our work, which is the first genome-wide gene expression study to investigate specific growth rate and consider the impact of oxygen availability, provides a more conservative estimate of growth rate dependent genes than previously reported. We also provide a global view of how a small set of transcription factors, 13 in total, contribute to control of cellular growth rate. We anticipate that multi-factorial designs will play an increasing role in elucidating cellular regulation.
authors.affiliation: Center for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, Building 223, DK-2800, Kgs, Lyngby, Denmark. alfa@cbs.dtu.dk
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fazio
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jewett
authors.forename: Pascale
authors.initials: P
authors.lastname: Daran-Lapujade
authors.forename: Roberta
authors.initials: R
authors.lastname: Mustacchi
authors.forename: Renata
authors.initials: R
authors.lastname: Usaite
authors.forename: Jack T
authors.initials: JT
authors.lastname: Pronk
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Workman
authors.forename: Jens
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D000332:Aerobiosis; D000693:Anaerobiosis; D002244:Carbon / Q000378:metabolism; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000235:genetics*; D005800:Genes, Fungal / Q000235:genetics*; D009584:Nitrogen / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012331:RNA, Fungal / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D012331:RNA, Fungal; D014157:Transcription Factors; D002244:Carbon; D009584:Nitrogen