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Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences
Y V Sun1, D R Boverhof, L D Burgoon
1Department of Biochemistry and Molecular Biology, National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824, USA.
Nucleic Acids Research
|August 26, 2004
Summary
Researchers identified dioxin response elements (DREs) across species, finding their distribution and function near genes are not well conserved. This suggests limitations in using animal models for human dioxin risk assessment.
Area of Science:
- Genomics
- Toxicology
- Molecular Biology
Background:
- Dioxin response elements (DREs) are crucial DNA sequences mediating the effects of dioxins.
- Understanding DRE conservation across species is vital for accurate toxicological risk assessment.
Purpose of the Study:
- To comparatively identify and analyze DREs in human, mouse, and rat genomes.
- To assess the conservation and functional relevance of DREs across species.
Main Methods:
- Utilized comparative genomics to identify DREs in RefSeq accessioned sequences.
- Developed a position weight matrix and matrix similarity score to rank DREs.
- Performed gene expression assays in mouse liver tissue to validate DRE function.
Main Results:
- Identified 13 bona fide DREs with a conserved core sequence (GCGTG).
- Found DREs disproportionately located near transcription start sites in all three species.
- Confirmed responsiveness of 192 genes with putative DREs and corroborated known DREs in Cyp1a1 and Cyp1b1.
- Identified conserved DREs in 19 orthologous genes, with 7 showing dioxin-mediated regulation, though with discrepancies between in vivo and in vitro data.
- Observed limited conservation of DRE-containing orthologous genes across human, mouse, and rat.
Conclusions:
- AhR-mediated gene expression shows limited conservation across species.
- Discrepancies in DRE conservation and regulation highlight challenges in extrapolating animal study findings to human risk assessment.
