title: Exploiting combinatorial cultivation conditions to infer transcriptional regulation.
abstract: BACKGROUND
  Regulatory networks often employ the model that attributes changes in gene expression levels, as observed across different cellular conditions, to changes in the activity of transcription factors (TFs). Although the actual conditions that trigger a change in TF activity should form an integral part of the generated regulatory network, they are usually lacking. This is due to the fact that the large heterogeneity in the employed conditions and the continuous changes in environmental parameters in the often used shake-flask cultures, prevent the unambiguous modeling of the cultivation conditions within the computational framework.
  
  
  RESULTS
  We designed an experimental setup that allows us to explicitly model the cultivation conditions and use these to infer the activity of TFs. The yeast Saccharomyces cerevisiae was cultivated under four different nutrient limitations in both aerobic and anaerobic chemostat cultures. In the chemostats, environmental and growth parameters are accurately controlled. Consequently, the measured transcriptional response can be directly correlated with changes in the limited nutrient or oxygen concentration. We devised a tailor-made computational approach that exploits the systematic setup of the cultivation conditions in order to identify the individual and combined effects of nutrient limitations and oxygen availability on expression behavior and TF activity.
  
  
  CONCLUSIONS
  Incorporating the actual growth conditions when inferring regulatory relationships provides detailed insight in the functionality of the TFs that are triggered by changes in the employed cultivation conditions. For example, our results confirm the established role of TF Hap4 in both aerobic regulation and glucose derepression. Among the numerous inferred condition-specific regulatory associations between gene sets and TFs, also many novel putative regulatory mechanisms, such as the possible role of Tye7 in sulfur metabolism, were identified.
authors.affiliation: Information and Communication Theory Group, Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Mekelweg 4, 2628 CD Delft, The Netherlands. t.a.knijnenburg@tudelft.nl
authors.forename: Theo A
authors.initials: TA
authors.lastname: Knijnenburg
authors.forename: Johannes H
authors.initials: JH
authors.lastname: de Winde
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Daran
authors.forename: Pascale
authors.initials: P
authors.lastname: Daran-Lapujade
authors.forename: Jack T
authors.initials: JT
authors.lastname: Pronk
authors.forename: Marcel J T
authors.initials: MJ
authors.lastname: Reinders
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
mesh_terms: D000332:Aerobiosis; D000693:Anaerobiosis; D001483:Base Sequence; D002874:Chromosome Mapping / Q000379:methods*; D019295:Computational Biology; D015870:Gene Expression; D016678:Genome / Q000235:genetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development*; D013455:Sulfur / Q000378:metabolism; D046509:Tissue Culture Techniques / Q000379:methods*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D014157:Transcription Factors; D013455:Sulfur