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M408395200v1
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Papers In Press, published online ahead of print August 16, 2004
J. Biol. Chem, 10.1074/jbc.M408395200
Submitted on July 26, 2004
Revised on August 13, 2004
Accepted on August 16, 2004

Development and refinement of pregnane X receptor DNA binding site model using information theory: Insights into PXR mediated gene regulation

Carrie A. Vyhlidal, Peter K. Rogan, and J. Steven Leeder

Division of Pediatric Clinical Pharmacology and Medical Toxicology, Children's Mercy Hospital and Clinics, Kansas City, Missouri 64108

Corresponding Author: sleeder{at}cmh.edu

The pregnane X receptor (PXR) acts as a receptor to induce gene expression in response to structurally diverse xenobiotics through binding as a heterodimer with the 9-cis retinoic acid receptor (RXR) to enhancers in target gene promoters. We identified and estimated the affinities of novel PXR/RXR binding sites in regulated genes and additional genomic targets of PXR with an information theory-based model of the PXR/RXR binding site. Our initial PXR/RXR model, the result of the alignment of 15 previously characterized binding sites, was used to scan the promoters of known PXR target genes. Sites from these genes with information contents >8 bits bound by PXR/RXR in vitro were used to revise the information weight matrix and this procedure was repeated by screening for progressively weaker binding sites. After three iterations of refinement, the model is based on 48 PXR/RXR binding sites and has an average information content (Rsequence) of 14.43±3.21 bits. A scan of the human genome predicted novel PXR/RXR binding sites in the promoters of UGT1A3 (19.78 bits at -8040 and 16.37 bits at -6930) and UGT1A6 (12.74 bits at -9216), both of which were previously identified as targets for PXR. These sites were subsequently demonstrated to specifically bind PXR/RXR in competition EMSAs. A strong PXR site was also predicted upstream of the CASP10 gene (18.69 bits at -7872) and validated by binding studies and reporter assays as a PXR responsive element. This suggests that the PXR-mediated response extends beyond genes involved in drug biotransformation and transport.


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