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Papers In Press, published online ahead of print July 1, 2006
J. Lipid Res., doi:10.1194/jlr.M500504-JLR200

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Journal of Lipid Research, Vol. 47, 1583-1587, July 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Methods

Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics

Danielle G. Lemay and Daniel H. Hwang¹

United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, and Department of Nutrition, University of California-Davis, Davis, CA 95616

The online version of this article (available at http://www.jlr.org) contains additional tables and references in 9 sections.

Published, JLR Papers in Press, April 3, 2006.

¹ To whom correspondence should be addressed. e-mail: dhwang{at}whnrc.usda.gov

Peroxisome proliferator-activated receptor (PPAR) agonists are currently used therapeutically in humans, even though many of their direct gene targets are unknown. Because PPARs can directly regulate gene expression through peroxisome proliferator response elements (PPREs), we pursued the computational prediction of PPREs on a genome-wide scale. Contrary to current hypotheses, PPREs are not isotype-specific, nor do flanking nucleotides confer additional information. However, a position weight matrix-based search for PPREs within upstream conserved elements yielded sufficient selectivity for a genome-wide search. Additionally, a novel motif occurring with greater prevalence than PPREs was revealed. Microarray and gene ontology analyses further validated our search technique and provided new functional clusters of genes that were not previously known to be directly regulated by PPARs (e.g., chromatin remodeling, DNA damage response, Wnt, and mitogen-activated protein kinase signaling). This first genome-wide library of high-confidence predicted PPAR target genes will be a valuable resource to PPAR biologists.

Supplementary key words peroxisome proliferator-activated receptor • target genes • conserved elements • PACM

Abbreviations: DR1, direct repeat with a 1 bp spacer; GO, gene ontology; GWM, generalized weight matrix; PACM, PPAR-associated conserved motif; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; PWM, position weight matrix; ROC, receiver operating characteristic; UCSC, University of California at Santa Cruz

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