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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Step, SE; Lim, HW; Marinis, JM; Prokesch, A; Steger, DJ; You, SH; Won, KJ; Lazar, MA.
Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers.
Genes Dev. 2014; 28(9): 1018-1028.
Doi: 10.1101/gad.237628.114
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- Co-Autor*innen der Med Uni Graz
- Prokesch Andreas
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- 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 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.
- Find related publications in this database (using NLM MeSH Indexing)
- 3T3-L1 Cells -
- Adipocytes - drug effects
- Animals -
- Gene Expression Regulation - drug effects
- Humans -
- Hypoglycemic Agents - pharmacology
- Mediator Complex Subunit 1 - metabolism
- Mice -
- PPAR gamma - metabolism
- Protein Binding -
- Thiazolidinediones - pharmacology
- Transcriptome -
- Find related publications in this database (Keywords)
- adipocyte
- diabetes
- rosiglitazone
- transcription
- PPAR gamma
- enhancer RNA