Bioinformatic analysis of gene sets regulated by ligand-activated and dominant-negative peroxisome proliferator-activated receptor gamma in mouse aorta. Arterioscler Thromb Vasc Biol 2010 Mar;30(3):518-25
Date
12/19/2009Pubmed ID
20018933Pubmed Central ID
PMC2850258DOI
10.1161/ATVBAHA.109.200733Scopus ID
2-s2.0-77649134985 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
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.
METHODS AND 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.
Author List
Keen HL, Halabi CM, Beyer AM, de Lange WJ, Liu X, Maeda N, Faraci FM, Casavant TL, Sigmund CDAuthors
Andreas M. Beyer PhD Professor in the Medicine department at Medical College of WisconsinCurt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAorta, Thoracic
Computational Biology
Gene Expression Profiling
Ligands
Mice
Mice, Inbred C57BL
Models, Animal
Mutation
PPAR gamma
Signal Transduction
Thiazolidinediones
Up-Regulation
