Genetics-Based Approach to Identify Novel Genes Regulated by the Aryl Hydrocarbon Receptor in Mouse Liver
| Autor: | David W. Threadgill, Peter Dornbos, Rance Nault, Amanda Jurgelewicz, Melanie Warren, Hui Lin, Anooj A Arkatkar, Timothy R. Zacharewski, John J. LaPres |
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| Rok vydání: | 2021 |
| Předmět: |
Molecular
Biochemical and Systems Toxicology 0301 basic medicine Polychlorinated Dibenzodioxins Toxicology Mice 03 medical and health sciences 0302 clinical medicine Inbred strain Genetic variation Animals Humans Allele Gene Transcription factor Regulation of gene expression Genetics biology respiratory system Aryl hydrocarbon receptor Phenotype 030104 developmental biology Liver Receptors Aryl Hydrocarbon 030220 oncology & carcinogenesis biology.protein Signal Transduction |
| Zdroj: | Toxicol Sci |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfab032 |
| Popis: | The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor in the Per-Arnt-Sim superfamily of environmental sensors that is linked to several metabolic diseases, including nonalcoholic fatty liver disease. Much remains unknown regarding the impact of genetic variation in AHR-driven disease, as past studies have focused on a small number of inbred strains. Recently, the presence of a wide range of interindividual variability amongst humans was reported in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the prototypical ligand of the AHR. In this study, a panel of 14 diverse mouse strains was exposed to TCDD for 10 days to characterize the AHR-mediated response across genetic backgrounds. Responses to TCDD are heavily dependent on genetic background. Although mice carry 1 of 4 Ahr alleles known to impact the affinity to AHR-ligands, we observed significant intra-allelic variability suggesting the presence of novel genetic modifiers of AHR signaling. A regression-based approach was used to scan for genes regulated by the AHR and/or associated with TCDD-induced phenotypes. The approach identified 7 genes, 2 of which are novel, that are likely regulated by the AHR based on association with hepatic TCDD burden (p ≤ .05). Finally, we identified 1 gene, Dio1, which was associated with change in percent body fat across the diverse set of strains (p ≤ .05). Overall, the results in this study exemplify the power of genetics-based approaches in identifying novel genes that are putatively regulated by the AHR. |
| Databáze: | OpenAIRE |
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