Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers
- Sonia E. Step1,2,3,4,8,
- Hee-Woong Lim4,5,8,
- Jill M. Marinis1,2,4,
- Andreas Prokesch1,2,4,6,7,
- David J. Steger1,2,4,
- Seo-Hee You1,2,4,
- Kyoung-Jae Won4,5 and
- Mitchell A. Lazar1,2,3,4,5,9
- 1Division of Endocrinology, Diabetes, and Metabolism,
- 2Department of Medicine,
- 3Department of Pharmacology,
- 4The Institute for Diabetes, Obesity, and Metabolism,
- 5Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 6Institute for Genomics and Bioinformatics,
- 7Institute of Biochemistry, Graz University of Technology, Graz 8010, Austria
Abstract
Rosiglitazone (rosi) is a powerful insulin sensitizer, but serious toxicities have curtailed its widespread clinical use. Rosi functions as a high-affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ), the adipocyte-predominant nuclear receptor (NR). The classic model, involving binding of ligand to the NR on DNA, explains positive regulation of gene expression, but ligand-dependent repression is not well understood. We addressed this issue by studying the direct effects of rosi on gene transcription using global run-on sequencing (GRO-seq). Rosi-induced changes in gene body transcription were pronounced after 10 min and correlated with steady-state mRNA levels as well as with transcription at nearby enhancers (enhancer RNAs [eRNAs]). Up-regulated eRNAs occurred almost exclusively at PPARγ-binding sites, to which rosi treatment recruited coactivators, including MED1, p300, and CBP. In contrast, transcriptional repression by rosi involved a loss of coactivators from eRNA sites devoid of PPARγ and enriched for other transcription factors, including AP-1 factors and C/EBPs. Thus, rosi activates and represses transcription by fundamentally different mechanisms that could inform the future development of anti-diabetic drugs.
Keywords
Footnotes
-
↵8 These authors contributed equally to this work.
-
↵9 Corresponding author
E-mail lazar{at}mail.med.upenn.edu
-
Supplemental material is available for this article.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.237628.114.
- Received January 9, 2014.
- Accepted March 31, 2014.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.