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. doi: 10.1161/ATVBAHA.109.200733. Epub 2009 Dec 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / metabolism*
  • Computational Biology*
  • Gene Expression Profiling*
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Mutation
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Rosiglitazone
  • Signal Transduction / physiology
  • Thiazolidinediones / pharmacology
  • Up-Regulation / drug effects

Substances

  • Ligands
  • PPAR gamma
  • Thiazolidinediones
  • Rosiglitazone

Grant support