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GENOME-WIDE ChIP-SEQ PROFILING OF PPARγ/RXR TARGET SITES AND GENE PROGRAM DURING 3T3-L1 ADIPOCYTE DIFFERENTIATION
Thomas Åskov Pedersen 1, Ronni Nielsen1, Dik Hagenbeek2 , Blaise Alako2, Rasmus Siersbæk1, Eva Megens2, Panagiotis Moulos2, Henk Stunnenberg2 and Susanne Mandrup1.
1Dept. Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark. 2Dept. of Molecular Biology, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands.
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which bind to DNA as heterodimers with members of the retinoid X receptor family. Numerous gain-of-function and loss of function experiments have unequivocally shown that PPARγ is a master regulator of and obligate for adipocyte differentiation. In addition to driving the adipogenic process, PPARγ activates directly a large number of genes involved in lipid storage and lipid turnover.
Using ChIP-sequencing we have generated a genome-wide map of PPARγ-RXR binding to chromatin as well as the activation of associated target genes during differentiation of murine 3T3-L1 adipocytes. Our analysis shows that target sites/genes attain RXR and PPARγ occupancy at different time points. Most of the known target genes have multiple binding sites within few kb from the promoter, and around 50% of these target sites are located in introns. These results provide an excellent basis for extensive analyses of the regulatory network controlled by PPARγ during adipocyte differentiation and in the mature adipocytes.
This work is supported by grants to the EU FP6 STREP project X-TRA-NET, EU FP6 IP HEROIC and grants from the Lundbeck Foundation and the Danish Natural Science Research Council.