title: Revealing cell cycle control by combining model-based detection of periodic expression with novel cis-regulatory descriptors.
abstract: BACKGROUND
  We address the issue of explaining the presence or absence of phase-specific transcription in budding yeast cultures under different conditions. To this end we use a model-based detector of gene expression periodicity to divide genes into classes depending on their behavior in experiments using different synchronization methods. While computational inference of gene regulatory circuits typically relies on expression similarity (clustering) in order to find classes of potentially co-regulated genes, this method instead takes advantage of known time profile signatures related to the studied process.
  
  
  RESULTS
  We explain the regulatory mechanisms of the inferred periodic classes with cis-regulatory descriptors that combine upstream sequence motifs with experimentally determined binding of transcription factors. By systematic statistical analysis we show that periodic classes are best explained by combinations of descriptors rather than single descriptors, and that different combinations correspond to periodic expression in different classes. We also find evidence for additive regulation in that the combinations of cis-regulatory descriptors associated with genes periodically expressed in fewer conditions are frequently subsets of combinations associated with genes periodically expression in more conditions. Finally, we demonstrate that our approach retrieves combinations that are more specific towards known cell-cycle related regulators than the frequently used clustering approach.
  
  
  CONCLUSIONS
  The results illustrate how a model-based approach to expression analysis may be particularly well suited to detect biologically relevant mechanisms. Our new approach makes it possible to provide more refined hypotheses about regulatory mechanisms of the cell cycle and it can easily be adjusted to reveal regulation of other, non-periodic, cellular processes.
authors.affiliation: The Linnaeus Centre for Bioinformatics, Uppsala University and Swedish University of Agricultural Sciences, Uppsala, Sweden. claes.andersson@lcb.uu.se
authors.forename: Claes R
authors.initials: CR
authors.lastname: Andersson
authors.forename: Torgeir R
authors.initials: TR
authors.lastname: Hvidsten
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.forename: Mats G
authors.initials: MG
authors.lastname: Gustafsson
authors.forename: Jan
authors.initials: J
authors.lastname: Komorowski
mesh_terms: D002453:Cell Cycle; D020869:Gene Expression Profiling; D005800:Genes, Fungal; D008954:Models, Biological; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics