Human Molecular Genetics Advance Access published online on April 4, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm066
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Published by Oxford University Press 2007
Identification of polymorphic antioxidant response elements (AREs) in the human genome
1 Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709 2 Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709 3 Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104
* To whom all correspondence should be addressed: Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Mail Drop: C3-03, 111 TW Alexander Drive, PO Box 12233, Research Triangle Park, NC 27709. Tel: 919-541-7686, Fax: 919-541-7593, E-mail: BELL1{at}niehs.nih.gov
Received January 3, 2007; Revised March 13, 2007; Accepted March 13, 2007
Single nucleotide polymorphisms (SNPs) in transcription factor binding sites (TFBSs) may affect the binding of transcription factors, lead to differences in gene expression and phenotypes, and therefore affect susceptibility to environmental exposure. We developed an integrated computational system for discovering functional SNPs in TFBSs in the human genome and predicting their impact on the expression of target genes. In this system we: (1) construct a position weight matrix (PWM) from a collection of experimentally discovered TFBSs; (2) predict TFBSs in SNP sequences using the PWM and map SNPs to the upstream regions of genes; (3) examine the evolutionary conservation of putative TFBSs by phylogenetic footprinting; (4) prioritize candidate SNPs based on microarray expression profiles from tissues in which the transcription factor of interest is either deleted or over-expressed; and (5) finally, analyze association of SNP genotypes with gene expression phenotypes. The application of our system has been tested to identify functional polymorphisms in the antioxidant response element (ARE), a cis-acting enhancer sequence found in the promoter region of many genes that encode antioxidant and Phase II detoxification enzymes/proteins. In response to oxidative stress, the transcription factor NRF2 (nuclear factor erythroid-derived 2-like 2) binds to AREs, mediating transcriptional activation of its responsive genes and modulating in vivo defense mechanisms against oxidative damage. Using our novel computational tools, we have identified a set of polymorphic AREs with functional evidence, showing the utility of our system to direct further experimental validation of genomic sequence variations that could be useful for identifying high-risk individuals.
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