Published online 24 August 2004
Nucleic Acids Research, Vol. 32 No. 15 © Oxford University Press 2004; all rights reserved
Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences
1 Department of Biochemistry and Molecular Biology, 2 Department of Pharmacology and Toxicology, 3 National Food Safety and Toxicology Center and 4 Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA
* To whom correspondence should be addressed. Tel: +1 517 355 1607; Fax: +1 517 353 9334; Email: tzachare{at}msu.edu
Present address: M. R. Fielden, Iconix Pharmaceuticals, Mountain View, CA 94043, USA
Received May 18, 2004; Revised June 24, 2004; Accepted August 3, 2004
Comparative approaches were used to identify human, mouse and rat dioxin response elements (DREs) in genomic sequences unambiguously assigned to a nucleotide RefSeq accession number. A total of 13 bona fide DREs, all including the substitution intolerant core sequence (GCGTG) and adjacent variable sequences, were used to establish a position weight matrix and a matrix similarity (MS) score threshold to rank identified DREs. DREs with MS scores above the threshold were disproportionately distributed in close proximity to the transcription start site in all three species. Gene expression assays in hepatic mouse tissue confirmed the responsiveness of 192 genes possessing a putative DRE. Previously identified functional DREs in well-characterized AhR-regulated genes including Cyp1a1 and Cyp1b1 were corroborated. Putative DREs were identified in 48 out of 2437 human–mouse–rat orthologous genes between –1500 and the transcriptional start site, of which 19 of these genes possessed positionally conserved DREs as determined by multiple sequence alignment. Seven of these nineteen genes exhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated regulation, although there were significant discrepancies between in vivo and in vitro results. Interestingly, of the mouse–rat orthologous genes with a DRE between –1500 and +1500, only 37% had an equivalent human ortholog. These results suggest that AhR-mediated gene expression may not be well conserved across species, which could have significant implications in human risk assessment.
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