Identification and Characterization of Genes Susceptible to Transcriptional Cross-Talk between the Hypoxia and Dioxin Signaling Cascades

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Abstract
The aryl hydrocarbon receptor (AHR) and hypoxia inducible factors (HIFs) are transcription factors that control the adaptive response to toxicants such as dioxins and decreases in available oxygen, respectively. The AHR and HIFs utilize the same heterodimeric partner, the aryl hydrocarbon nuclear translocator (ARNT) for proper function. This requirement raises the possibility that cross-talk exists between these critical signaling systems. Single gene and reporter assays have yielded conflicting results regarding the nature of the competition for ARNT. Therefore, to determine the extent of cross-talk between the AHR and HIFs, a comprehensive analysis was performed using global gene expression analysis. The results identified 767 and 430 transcripts that are sensitive to cobalt chloride and 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD) stimulation, respectively, with 308 and 176, respectively, exhibiting sensitivity to cross-talk. The overlap between these two sets consists of 33 unique transcripts, including the classic target genes CYP1A1, carbonic anhydrase IX, and those involved in lipid metabolism and coagulation. Computational analysis of the regulatory region of these genes identified complex relationships between HIFs, AHR, and their respective response elements as well as other DNA motifs, including the SRF, Sp-1, NF-kB, and AP-2 binding sites. These results suggest that HIF−AHR cross-talk is limited to genes with regulatory regions that contain specific motifs and architectures.