PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale

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Abstract
Peroxisome proliferator-activated receptor γ(PPARγ), a nuclear receptor and the target of anti-diabetic thiazolinedione drugs, is known as the master regulator of adipocyte biology. Although it regulates hundreds of adipocyte genes, PPARγ binding to endogenous genes has rarely been demonstrated. Here, utilizing chromatin immunoprecipitation (ChIP) coupled with whole genome tiling arrays, we identified 5299 genomic regions of PPARγ binding in mouse 3T3-L1 adipocytes. The consensus PPARγ/RXRα “DR-1”-binding motif was found at most of the sites, and ChIP for RXRα showed colocalization at nearly all locations tested. Bioinformatics analysis also revealed CCAAT/enhancer-binding protein (C/EBP)-binding motifs in the vicinity of most PPARγ-binding sites, and genome-wide analysis of C/EBPα binding demonstrated that it localized to 3350 of the locations bound by PPARγ. Importantly, most genes induced in adipogenesis were bound by both PPARγ and C/EBPα, while very few were PPARγ-specific. C/EBPβ also plays a role at many of these genes, such that both C/EBPα and β are required along with PPARγ for robust adipocyte-specific gene expression. Thus, PPARγ and C/EBP factors cooperatively orchestrate adipocyte biology by adjacent binding on an unanticipated scale.