title: Functional pathway mapping analysis for hypoxia-inducible factors.
abstract: BACKGROUND
  Hypoxia-inducible factors (HIFs) are transcription factors that play a crucial role in response to hypoxic stress in living organisms. The HIF pathway is activated by changes in cellular oxygen levels and has significant impacts on the regulation of gene expression patterns in cancer cells. Identifying functional conservation across species and discovering conserved regulatory motifs can facilitate the selection of reference species for empirical tests. This paper describes a cross-species functional pathway mapping strategy based on evidence of homologous relationships that employs matrix-based searching techniques for identifying transcription factor-binding sites on all retrieved HIF target genes.
  
  
  RESULTS
  HIF-related orthologous and paralogous genes were mapped onto the conserved pathways to indicate functional conservation across species. Quantitatively measured HIF pathways are depicted in order to illustrate the extent of functional conservation. The results show that in spite of the evolutionary process of speciation, distantly related species may exhibit functional conservation owing to conservative pathways. The novel terms OrthRate and ParaRate are proposed to quantitatively indicate the flexibility of a homologous pathway and reveal the alternative regulation of functional genes.
  
  
  CONCLUSIONS
  The developed functional pathway mapping strategy provides a bioinformatics approach for constructing biological pathways by highlighting the homologous relationships between various model species. The mapped HIF pathways were quantitatively illustrated and evaluated by statistically analyzing their conserved transcription factor-binding elements.
  
  
  BACKGROUND
  hypoxia-inducible factor (HIF), hypoxia-response element (HRE), transcription factor (TF), transcription factor binding site (TFBS), KEGG (Kyoto Encyclopedia of Genes and Genomes), cross-species comparison, orthology, paralogy, functional pathway.
authors.affiliation: Department of Computer Science and Engineering, and Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, No, 2 Peining Road, Keelung, Taiwan, R.O.C.
authors.forename: Chia-Sheng
authors.initials: CS
authors.lastname: Chuang
authors.forename: Tun-Wen
authors.initials: TW
authors.lastname: Pai
authors.forename: Chin-Hua
authors.initials: CH
authors.lastname: Hu
authors.forename: Wen-Shyong
authors.initials: WS
authors.lastname: Tzou
authors.forename: Margaret
authors.initials: M
authors.lastname: Dah-Tsyr Chang
authors.forename: Hao-Teng
authors.initials: HT
authors.lastname: Chang
authors.forename: Chih-Chia
authors.initials: CC
authors.lastname: Chen
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D017124:Conserved Sequence / Q000235:genetics; D030541:Databases, Genetic; D006801:Humans; D051379:Mice; D020218:Response Elements / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity
chemical_list: D051792:Basic Helix-Loop-Helix Proteins