Peroxisome proliferator-activated receptor subtype- and cell-type-specific activation of genomic target genes upon adenoviral transgene delivery
Abstract
Investigations of the molecular events involved in activation of genomic target genes by peroxisome proliferator-activated receptors (PPARs) have been hampered by the inability to establish a clean on/off state of the receptor in living cells. Here we show that the combination of adenoviral delivery and chromatin immunoprecipitation (ChIP) is ideal for dissecting these mechanisms. Adenoviral delivery of PPARs leads to a rapid and synchronous expression of the PPAR subtypes, establishment of transcriptional active complexes at genomic loci, and immediate activation of even silent target genes. We demonstrate that PPARgamma2 possesses considerable ligand-dependent as well as independent transactivation potential and that agonists increase the occupancy of PPARgamma2/retinoid X receptor at PPAR response elements. Intriguingly, by direct comparison of the PPARs (alpha, gamma, and beta/delta), we show that the subtypes have very different abilities to gain access to target sites and that in general the genomic occupancy correlates with the ability to activate the corresponding target gene. In addition, the specificity and potency of activation by PPAR subtypes are highly dependent on the cell type. Thus, PPAR subtype-specific activation of genomic target genes involves an intricate interplay between the properties of the subtype- and cell-type-specific settings at the individual target loci.
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GW9662 is known as a selective PPARγ antagonist and is widely accepted to demonstrate participation of PPARγ in signaling cascades.
“GW9662, known as a selective peroxisome proliferator (PPAR)g antagonist, is widely accepted to demonstrate participation of PPARg in signaling cascades (Leesnitzer et al., 2002;Lea et al., 2004;Nielsen et al., 2006).”
The expression of PPAR target genes is dependent on the differential expression of the PPAR subtypes in cells as well as the setting of the target sites, such as chromatin modification and the combination of other transcription factors, which is highly cell-type specific.
“The expression of PPAR target genes is undoubtedly dependent on the differential expression of the PPAR subtypes in cells as well as the”
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- Authors
- Nielsen, R., Grøntved, L., Stunnenberg, H. G., & Mandrup, S.
- Affiliations
- University of Southern Denmark (DK)
- Radboud University Nijmegen (NL)
- Corresponding author
- Mandrup, Susanne
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-08-01
- Volume
- 26
- Issue
- 15
- Pages
- 5698-5714
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2121241298
- Cited by
- 77
- References
- 5
- Citations by year
- 2026: 2 · 2023: 2 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 2 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 8 · 2012: 11
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Lundbeckfonden
- Novo Nordisk
- Diabetesforeningen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- peroxisome proliferator-activated receptors, PPARγ2, PPARα, PPARδ, transcriptional activation, chromatin immunoprecipitation, retinoid X receptor, PPAR response element, cell type-specific gene regulation, transcriptional complex
- MeSH terms
- Adenoviridae, Animals, Cell Line, Fibroblasts, Genetic Vectors, Ligands, Mice, Inbred C57BL, Transcriptional Activation, Gene Transfer Techniques, Transgenes, Protein Isoforms, Gene Expression Profiling, Chromatin Immunoprecipitation, Peroxisome Proliferator-Activated Receptors, Mice
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