Abstract
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
Highlights
Hypoxia-inducible factors (HIFs) are transcription factors that play a crucial role in response to hypoxic stress in living organisms
Mapping HIF pathways among various species Based on the evidence of evolutionary conservation in genetic sequences and functions, it is reasonable to assume that the functional pathways of a given species could be mapped by cross-species inference
Using human renal cell carcinoma (KEGG pathway: hsa05211) as an example while focusing on the HIF subpathway shown in Figure 1, a total of 14 genes are displayed in the rectangular boxes, which are correlated with the HIF transcriptional complex and respond to changes in cellular oxygen levels
Summary
Hypoxia-inducible factors (HIFs) are transcription factors that play a crucial role in response to hypoxic stress in living organisms. 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 factorbinding sites on all retrieved HIF target genes. It is a challenge for aerobic life to maintain oxygen homoeostasis due to environmental changes and energy demands. The consensus HRE motif is a cis-regulatory element with a core segment of 5′RCGTG3′ (where R is A or G) [6] that governs the transcription of HIF-responsive target genes in the hypoxia-signaling pathway such as those encoding proteins involved in oxygen transport, iron metabolism, glucose transport, cell proliferation, angiogenesis, invasion, and metastasis [7,8]. The inhibition of HIF-1 expression or activity is an alternative strategy in new cancer therapies [9]
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