Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers
| Autor: | Kyoung-Jae Won, David J. Steger, Jill M. Marinis, Mitchell A. Lazar, Sonia E. Step, Hee-Woong Lim, Andreas Prokesch, Seo-Hee You |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Peroxisome proliferator-activated receptor Enhancer RNAs Biology MED1 Rosiglitazone Mediator Complex Subunit 1 Mice Transcription (biology) Internal medicine 3T3-L1 Cells Genetics medicine Adipocytes Animals Humans Hypoglycemic Agents Enhancer Transcription factor Regulation of gene expression chemistry.chemical_classification Cell biology PPAR gamma Endocrinology chemistry Nuclear receptor Gene Expression Regulation Thiazolidinediones Transcriptome Developmental Biology Research Paper Protein Binding |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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