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

TY - JOUR

T1 - Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers

AU - Step, Sonia E

AU - Lim, Hee-Woong

AU - Marinis, Jill M

AU - Prokesch, Andreas

AU - Steger, David J

AU - You, Seo-Hee

AU - Won, Kyoung-Jae

AU - Lazar, Mitchell A

PY - 2014/5/1

Y1 - 2014/5/1

N2 - 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.

AB - 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.

KW - 3T3-L1 Cells

KW - Adipocytes/drug effects

KW - Animals

KW - Gene Expression Regulation/drug effects

KW - Humans

KW - Hypoglycemic Agents/pharmacology

KW - Mediator Complex Subunit 1/metabolism

KW - Mice

KW - PPAR gamma/metabolism

KW - Protein Binding

KW - Thiazolidinediones/pharmacology

KW - Transcriptome

U2 - 10.1101/gad.237628.114

DO - 10.1101/gad.237628.114

M3 - Journal article

C2 - 24788520

SN - 0890-9369

VL - 28

SP - 1018

EP - 1028

JO - Genes & Development

JF - Genes & Development

IS - 9

ER -