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A Global Genomic and Genetic Strategy to Identify, Validate and Use Gene Signatures of Xenobiotic-Responsive Transcription Factors in Prediction of Pathway Activation in the Mouse Liver
Citation:
Oshida, K., N. Vasani, M. Rosen, B. D. ABBOTT, C. LAU, B. N. CHORLEY, S. Hester, G. Guo, T. Kensler, C. Klaassen, AND C. CORTON. A Global Genomic and Genetic Strategy to Identify, Validate and Use Gene Signatures of Xenobiotic-Responsive Transcription Factors in Prediction of Pathway Activation in the Mouse Liver. Presented at International Society for the Study of Xenobiotics (ISSX), Atlanta, GA, October 16 - 20, 2011.
Impact/Purpose:
Our approach allows for creation of new gene signatures associated with other pathways or phenomenon in the mouse liver that can be tested using the compendium. We are presently using the signature sets to predict pathway activation after chemical exposure in mouse primary hepatocytes
Description:
Many drugs and environmentally-relevant chemicals activate xenobiotic-responsive transcription factors. Identification of target genes of these factors would be useful in predicting pathway activation in in vitro chemical screening as well as their involvement in disease states. Starting with a large compendium of Affymetrix files (>2000), we developed a genetic and genomic strategy to identify sets of signature genes that are dependent on specific transcription factors (TF) including PPARalpha, CAR, PXR, AhR, Nrf2, FXR, and glucocorticoid receptor. Target genes were identified by comparing the profiles after exposure to activators of a TF in wild-type and TF-null mice. In most cases, we used three chemical comparisons to identify common gene targets that were characterized in terms of the average fold-change response to chemical exposure. In addition, we used the mouse liver compendium to identify sets of genes associated with phenomenon that are linked to liver toxicity/cancer including feminization/masculinization, hypoxia, inflammation and cytotoxicity. Validation of the identified genes was carried out by characterization of the expression of the signature genes under independent conditions of chemical exposure or perturbation known to alter the TF. By using the sets of signature genes to query the compendium, a number ofnovel observations were made. 1) PPARalpha is activated in a large number of nullizygous mouse models that also lead to liver toxicity and may be dependent on steatosis. 2) PXR and PPARalpha activation appear to be intertwined. Activation of PPARalpha leads to activation of PXR, sometimes in a PPAR alpha-dependent manner. 3) Nrf2 is activated by a large number of conditions including environmentally relevant chemicals, gene mutations, and bacterial infections. 4) GR is activated by a number of conditions including caloric restriction, and systemic damage outside the liver. 5) Feminization of male-specific signature genes occurred after castration, in GH-defective dwarf mice, bacterial infections and exposure to some chemicals while masculinization of the female-specific signature genes occurred by testosterone injection and chemical exposure. Our approach allows for creation of new gene signatures associated with other pathways or phenomenon in the mouse liver that can be tested using the compendium. We are presently using the signature sets to predict pathway activation after chemical exposure in mouse primary hepatocytes. (This abstract does not represent EPA policy)