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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 b...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018489/ https://www.ncbi.nlm.nih.gov/pubmed/24788520 http://dx.doi.org/10.1101/gad.237628.114 |
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author | Step, Sonia E. Lim, Hee-Woong Marinis, Jill M. Prokesch, Andreas Steger, David J. You, Seo-Hee Won, Kyoung-Jae Lazar, Mitchell A. |
author_facet | Step, Sonia E. Lim, Hee-Woong Marinis, Jill M. Prokesch, Andreas Steger, David J. You, Seo-Hee Won, Kyoung-Jae Lazar, Mitchell A. |
author_sort | Step, Sonia E. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4018489 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-40184892014-11-01 Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers Step, Sonia E. Lim, Hee-Woong Marinis, Jill M. Prokesch, Andreas Steger, David J. You, Seo-Hee Won, Kyoung-Jae Lazar, Mitchell A. Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2014-05-01 /pmc/articles/PMC4018489/ /pubmed/24788520 http://dx.doi.org/10.1101/gad.237628.114 Text en © 2014 Step et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Paper Step, Sonia E. Lim, Hee-Woong Marinis, Jill M. Prokesch, Andreas Steger, David J. You, Seo-Hee Won, Kyoung-Jae Lazar, Mitchell A. Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers |
title | Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers |
title_full | Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers |
title_fullStr | Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers |
title_full_unstemmed | Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers |
title_short | Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers |
title_sort | anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to pparγ-driven enhancers |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018489/ https://www.ncbi.nlm.nih.gov/pubmed/24788520 http://dx.doi.org/10.1101/gad.237628.114 |
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