Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers.
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.
Division of Endocrinology, Diabetes, and Metabolism.
Sonia E
SE
Step
Hee-Woong
HW
Lim
Jill M
JM
Marinis
Andreas
A
Prokesch
David J
DJ
Steger
Seo-Hee
SH
You
Kyoung-Jae
KJ
Won
Mitchell A
MA
Lazar
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D056913:Mediator Complex Subunit 1 / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D011485:Protein Binding; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D059467:Transcriptome
D007004:Hypoglycemic Agents; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
PPARγ; adipocyte; diabetes; enhancer RNA; rosiglitazone; transcription