Selective modulation of promoter recruitment and transcriptional activity of PPARgamma.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor regulated by the insulin-sensitizing thiazolidinediones (TZDs). We studied selective modulation of endogenous genes by PPARgamma ligands using microarray, RNA expression kinetics, and chromatin immunoprecipitation (ChIP) in 3T3-L1 adipocytes. We found over 300 genes that were significantly regulated the TZDs pioglitazone, rosiglitazone, and troglitazone. TZD-mediated expression profiles were unique but overlapping. Ninety-one genes were commonly regulated by all three ligands. TZD time course and dose-response studies revealed gene- and TZD-specific expression kinetics. PEPCK expression was induced rapidly but PDK4 expression was induced gradually. Troglitazone EC50 values for PEPCK, PDK4, and RGS2 regulation were greater than those for pioglitazone and rosiglitazone. TZDs differentially induced histone acetylation of and PPARgamma recruitment to target gene promoters. Selective modulation of PPARgamma by TZDs resulted in distinct expression profiles and transcription kinetics which may be due to differential promoter activation and chromatin remodeling of target genes.
Sears
Dorothy D
DD
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, MC0673, La Jolla, CA 92093, USA. dsears@ucsd.edu
Hsiao
Albert
A
Ofrecio
Jachelle M
JM
Chapman
Justin
J
He
Weimin
W
Olefsky
Jerrold M
JM
D041721:3T3-L1 Cells; D000818:Animals; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D047495:PPAR gamma / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
D047495:PPAR gamma