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Molecular and Cellular Biology, August 2006, p. 5698-5714, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.02266-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Peroxisome Proliferator-Activated Receptor Subtype- and Cell-Type-Specific Activation of Genomic Target Genes upon Adenoviral Transgene Delivery

Ronni Nielsen,^1, Lars Grøntved,^1, Hendrik G. Stunnenberg,² and Susanne Mandrup^1*

Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark,¹ Department of Molecular Biology, Nijmegen Center for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, The Netherlands²

Received 25 November 2005/ Returned for modification 2 January 2006/ Accepted 16 May 2006

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 PPAR2 possesses considerable ligand-dependent as well as independent transactivation potential and that agonists increase the occupancy of PPAR2/retinoid X receptor at PPAR response elements. Intriguingly, by direct comparison of the PPARs (, , and ß/), 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.

R.N. and L.G. contributed equally to the work.

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