Differential gene regulation by the human and mouse aryl hydrocarbon receptor.
The human aryl hydrocarbon receptor (hAHR) and mouse aryl hydrocarbon receptor (mAHR(b)) share limited (58%) transactivation domain (TAD) sequence identity. Compared to the mAHR(b) allele, the hAHR displays 10-fold lower relative affinity for prototypical ligands, such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). However, in previous studies, we have demonstrated that the hAHR can display a higher relative ligand-binding affinity than the mAHR(b) for specific AHR ligands, such as indirubin. Each receptor has also been shown to differentially recruit LXXLL coactivator motif proteins and to utilize different TAD subdomains in gene transactivation. Using hepatocytes isolated from C57BL/6J mice (Ahr(b/b)) and AHR(Ttr) transgenic mice, which express hAHR protein specifically in hepatocytes, we investigated whether the hAHR and mAHR(b) differentially regulate genes. DNA microarray and quantitative PCR analysis of Ahr(b/b) and AHR(Ttr) primary mouse hepatocytes treated with 10nM TCDD revealed that a number of established AHR target genes such as Cyp1a1 and Cyp1b1 are significantly induced by both receptors. Remarkably, of the 1752 genes induced by mAHR(b) and 1186 genes induced by hAHR, only 265 genes (approximately 18%) were significantly activated by both receptors in response to TCDD. Conversely, of the 1100 and 779 genes significantly repressed in mAHR(b) and hAHR hepatocytes, respectively, only 462 (approximately 49%) genes were significantly repressed by both receptors in response to TCDD treatment. Genes identified as differentially expressed are known to be involved in a number of biological pathways, including cell proliferation and inflammatory response, which suggest that compared to the mAHR(b), the hAHR may play contrasting roles in TCDD-induced toxicity and endogenous AHR-mediated gene regulation.
Flaveny
Colin A
CA
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Murray
Iain A
IA
Perdew
Gary H
GH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D049109:Cell Proliferation / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics*; D013045:Species Specificity
D051792:Basic Helix-Loop-Helix Proteins; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C484722:Ahr protein, mouse