Transcriptomics,Genomics

Dataset Information

302

Antidiabetic Rosiglitazone Remodels the Adipocyte Transcriptome by Redistributing Transcription to PPARg-Driven Enhancers [HTS]


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 PPARg, 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 have now addressed this issue by studying the direct effects of rosiglitazone on gene transcription, using global run-on sequencing (GRO-seq). Rosi-induced changes in gene body transcription were pronounced after 10 minutes and correlated with steady-state mRNA levels as well as with transcription at nearby enhancers (eRNAs). Upregulated eRNAs occurred almost exclusively at PPARg binding sites, to which rosi treatment recruited the coactivator MED1. By contrast, transcriptional repression by rosi involved a loss of MED1 from eRNA sites devoid of PPARg and enriched for other TFs including AP-1 factors and C/EBPs. Thus, rosi activates and represses transcription by fundamentally different mechanisms that could inform the future development of antidiabetic drugs. 3T3-L1 matuer adipocyte were treated with rosi, and nascent transcripts were measured at various time points using GRO-seq. ChIP-seq experiments for various coactivators, corepressor, and transcription factors also have been done to monitor initial occupancy or change before and after treatment.

ORGANISM(S): Mus musculus  

SUBMITTER: Hee-Woong Lim   Mitchell A Lazar  Jill M Marinis  Kyoung-Jae Won  Sonia E Step  David J Steger  Andreas Prokesch  Seo-Hee You 

PROVIDER: E-GEOD-56745 | ArrayExpress | 2014-05-02

SECONDARY ACCESSION(S): SRP041129GSE56745PRJNA244432

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

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

Step Sonia E SE   Lim Hee-Woong HW   Marinis Jill M JM   Prokesch Andreas A   Steger David J DJ   You Seo-Hee SH   Won Kyoung-Jae KJ   Lazar Mitchell A MA  

Genes & development 20140501 9


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 ro  ...[more]

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