Functional pathway mapping analysis for hypoxia-inducible factors

BackgroundHypoxia-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.ResultsHIF-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.ConclusionThe 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.Keywordshypoxia-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

[1]  Jong-Wan Park,et al.  New anticancer strategies targeting HIF-1. , 2004, Biochemical pharmacology.

[2]  R. Wenger,et al.  Cellular adaptation to hypoxia: O2‐sensing protein hydroxylases, hypoxia‐inducible transcription factors, and O2‐regulated gene expression , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  Michael Y. Galperin,et al.  The COG database: new developments in phylogenetic classification of proteins from complete genomes , 2001, Nucleic Acids Res..

[4]  Holger Karas,et al.  TRANSFAC: a database on transcription factors and their DNA binding sites , 1996, Nucleic Acids Res..

[5]  Yoshihiro Yamanishi,et al.  KEGG for linking genomes to life and the environment , 2007, Nucleic Acids Res..

[6]  Corinne Da Silva,et al.  Phylogenomics Revives Traditional Views on Deep Animal Relationships , 2009, Current Biology.

[7]  G. Semenza,et al.  Dimerization, DNA Binding, and Transactivation Properties of Hypoxia-inducible Factor 1* , 1996, The Journal of Biological Chemistry.

[8]  J. Raes,et al.  Gene duplication, the evolution of novel gene functions, and detecting functional divergence of duplicates in silico. , 2003, Applied bioinformatics.

[9]  Steven J. M. Jones,et al.  Locating mammalian transcription factor binding sites: a survey of computational and experimental techniques. , 2006, Genome research.

[10]  Roded Sharan,et al.  Improved network-based identification of protein orthologs , 2008, ECCB.

[11]  Gultekin Özsoyoglu,et al.  Mining biological networks for unknown pathways , 2007, Bioinform..

[12]  Alexander E. Kel,et al.  TRANSFAC®: transcriptional regulation, from patterns to profiles , 2003, Nucleic Acids Res..

[13]  Gary D. Stormo,et al.  enoLOGOS: a versatile web tool for energy normalized sequence logos , 2005, Nucleic Acids Res..

[14]  Abha Meena,et al.  D-MATRIX: A web tool for constructing weight matrix of conserved DNA motifs , 2009, Bioinformation.

[15]  D. Kell,et al.  The Kyoto Encyclopedia of Genes and Genomes—KEGG , 2000, Yeast.

[16]  G. Semenza,et al.  Life with Oxygen , 2007, Science.

[17]  G. Semenza.  Signal transduction to hypoxia-inducible factor 1. , 2002, Biochemical pharmacology.

[18]  Jong-Wan Park,et al.  Oxygen-dependent and -independent regulation of HIF-1alpha. , 2002, Journal of Korean medical science.

[19]  G. Camenisch,et al.  Integration of Oxygen Signaling at the Consensus HRE , 2005, Science's STKE.

[20]  Cell Signaling: Details, Details, Details , 2007, Science's STKE.

[21]  P. Schumacker,et al.  Hypoxia-inducible factor-1 (HIF-1). , 2005, Critical care medicine.

[22]  G. Semenza,et al.  FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. , 2001 .

[23]  W. Kaelin,et al.  HIF hydroxylation and the mammalian oxygen-sensing pathway. , 2003, The Journal of clinical investigation.

[24]  Ikuo Uchiyama,et al.  Evolution of paralogous genes: Reconstruction of genome rearrangements through comparison of multiple genomes within Staphylococcus aureus. , 2006, Molecular biology and evolution.

[25]  G. Semenza,et al.  Hypoxia-Inducible Factor 1 (HIF-1) Pathway , 2007, Science's STKE.