Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers

• Published in: Genes & development Vol. 28; no. 9; pp. 1018 - 1028
• Main Authors: Step, Sonia E, Lim, Hee-Woong, Marinis, Jill M, Prokesch, Andreas, Steger, David J, You, Seo-Hee, Won, Kyoung-Jae, Lazar, Mitchell A
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.05.2014
• Subjects: 3T3-L1 Cells; Adipocytes - drug effects; Animals; Gene Expression Regulation - drug effects; Humans; Hypoglycemic Agents - pharmacology; Mediator Complex Subunit 1 - metabolism; Mice; PPAR gamma - metabolism; Protein Binding; Research Paper; Thiazolidinediones - pharmacology; Transcriptome; enhancer RNA; rosiglitazone; transcription; diabetes; PPARγ; adipocyte
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.237628.114

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.