Genome-wide profiling of PPARγ:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis

Ronni Nielsen, Thomas Åskov Pedersen, Dik Hagenbeek, Panagiotis Moulos, Rasmus Siersbæk, Eva Megens, Sergei Denissov, Michael Børgesen, Kees Jan Francoijs, Susanne Mandrup, Hendrik G. Stunnenberg

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

454 Citaten (Scopus)

Samenvatting

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of adipocyte differentiation in vivo and ex vivo and has been shown to control the expression of several adipocyte-specific genes. In this study, we used chromatin immunoprecipitation combined with deep sequencing to generate genome-wide maps of PPARγ and retinoid X receptor (RXR)-binding sites, and RNA polymerase II (RNAPII) occupancy at very high resolution throughout adipocyte differentiation of 3T3-L1 cells. We identify >5000 high-confidence shared PPARγ:RXR-binding sites in adipocytes and show that during early stages of differentiation, many of these are preoccupied by non-PPARγ RXR-heterodimers. Different temporal and compositional patterns of occupancy are observed. In addition, we detect co-occupancy with members of the C/EBP family. Analysis of RNAPII occupancy uncovers distinct clusters of similarly regulated genes of different biological processes. PPARγ:RXR binding is associated with the majority of induced genes, and sites are particularly abundant in the vicinity of genes involved in lipid and glucose metabolism. Our analyses represent the first genome-wide map of PPARγ:RXR target sites and changes in RNAPII occupancy throughout adipocyte differentiation and indicate that a hitherto unrecognized high number of adipocyte genes of distinctly regulated pathways are directly activated by PPARγ:RXR.

Originele taal-2Engels
Pagina's (van-tot)2953-2967
Aantal pagina's15
TijdschriftGenes and Development
Volume22
Nummer van het tijdschrift21
DOI's
StatusGepubliceerd - 1 nov. 2008
Extern gepubliceerdJa

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