title: Integration of genome-wide computation DRE search, AhR ChIP-chip and gene expression analyses of TCDD-elicited responses in the mouse liver.
abstract: BACKGROUND
  The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor (TF) that mediates responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Integration of TCDD-induced genome-wide AhR enrichment, differential gene expression and computational dioxin response element (DRE) analyses further elucidate the hepatic AhR regulatory network.
  
  
  RESULTS
  Global ChIP-chip and gene expression analyses were performed on hepatic tissue from immature ovariectomized mice orally gavaged with 30 μg/kg TCDD. ChIP-chip analysis identified 14,446 and 974 AhR enriched regions (1% false discovery rate) at 2 and 24 hrs, respectively. Enrichment density was greatest in the proximal promoter, and more specifically, within ± 1.5 kb of a transcriptional start site (TSS). AhR enrichment also occurred distal to a TSS (e.g. intergenic DNA and 3' UTR), extending the potential gene expression regulatory roles of the AhR. Although TF binding site analyses identified over-represented DRE sequences within enriched regions, approximately 50% of all AhR enriched regions lacked a DRE core (5'-GCGTG-3'). Microarray analysis identified 1,896 number of TCDD-responsive genes (|fold change| ≥ 1.5, P1(t) > 0.999). Integrating this gene expression data with our ChIP-chip and DRE analyses only identified 625 differentially expressed genes that involved an AhR interaction at a DRE. Functional annotation analysis of differentially regulated genes associated with AhR enrichment identified overrepresented processes related to fatty acid and lipid metabolism and transport, and xenobiotic metabolism, which are consistent with TCDD-elicited steatosis in the mouse liver.
  
  
  CONCLUSIONS
  Details of the AhR regulatory network have been expanded to include AhR-DNA interactions within intragenic and intergenic genomic regions. Moreover, the AhR can interact with DNA independent of a DRE core suggesting there are alternative mechanisms of AhR-mediated gene regulation.
authors.affiliation: Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Dere
authors.forename: Raymond
authors.initials: R
authors.lastname: Lo
authors.forename: Trine
authors.initials: T
authors.lastname: Celius
authors.forename: Jason
authors.initials: J
authors.lastname: Matthews
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Zacharewski
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D021901:DNA, Intergenic / Q000235:genetics; D004785:Environmental Pollutants / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D005821:Genetic Techniques; D023281:Genomics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D059372:Nucleotide Motifs / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D018511:Systems Integration
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D021901:DNA, Intergenic; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon