Bioinformatic analysis of gene sets regulated by ligand-activated and dominant-negative peroxisome proliferator-activated receptor gamma in mouse aorta.
OBJECTIVE
Drugs that activate peroxisome proliferator-activated receptor (PPAR) gamma improve glucose sensitivity and lower blood pressure, whereas dominant-negative mutations in PPARgamma cause severe insulin resistance and hypertension. We hypothesize that these PPARgamma mutants regulate target genes opposite to those of ligand-mediated activation, and we tested this hypothesis on a genomewide scale.


RESULTS
We integrated gene expression data in aorta specimens from mice treated with the PPARgamma ligand rosiglitazone with data from mice containing a globally expressed knockin of the PPARgamma P465L dominant-negative mutation. We also integrated our data with publicly available data sets containing the following: (1) gene expression profiles in many human tissues, (2) PPARgamma target genes in 3T3-L1 adipocytes, and (3) experimentally validated PPARgamma binding sites throughout the genome. Many classic PPARgamma target genes were induced by rosiglitazone and repressed by dominant-negative PPARgamma. A similar pattern was observed for about 90% of the gene sets regulated by both rosiglitazone and dominant-negative PPARgamma. Genes exhibiting this pattern of contrasting regulation were significantly enriched for nearby PPARgamma binding sites.


CONCLUSIONS
These results provide convincing evidence that the PPARgamma P465L mutation causes transcriptional effects that are opposite to those mediated by PPARgamma ligand, thus validating mice carrying the mutation as a model of PPARgamma interference.
Keen
Henry L
HL
Department of Internal Medicine and Department of Molecular Physiology and Biophysics, 3181B Medical Education and Biomedical Research Facility, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Halabi
Carmen M
CM
Beyer
Andreas M
AM
de Lange
Willem J
WJ
Liu
Xuebo
X
Maeda
Nobuyo
N
Faraci
Frank M
FM
Casavant
Thomas L
TL
Sigmund
Curt D
CD
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism*; D019295:Computational Biology; D020869:Gene Expression Profiling; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009154:Mutation; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone