Profiling of promoter occupancy by PPARa in human hepatoma cells via ChIP-chip analysis

The transcription factor peroxisome proliferator-activated receptor a (PPARa) is an important regulator of hepatic lipid metabolism. While PPARa is known to activate transcription of numerous genes, no comprehensive picture of PPARa binding to endogenous genes has yet been reported. To fill this gap, we performed Chromatin immunoprecipitation (ChIP)-chip in combination with transcriptional profiling on HepG2 human hepatoma cells treated with the PPARa agonist GW7647. We found that GW7647 increased PPARa binding to 4220 binding regions. GW7647-induced binding regions showed a bias around the transcription start site and most contained a predicted PPAR binding motif. Several genes known to be regulated by PPARa, such as ACOX1, SULT2A1, ACADL, CD36, IGFBP1 and G0S2, showed GW7647-induced PPARa binding to their promoter. A GW7647-induced PPARa-binding region was also assigned to SREBP-targets HMGCS1, HMGCR, FDFT1, SC4MOL, and LPIN1, expression of which was induced by GW7647, suggesting cross-talk between PPARa and SREBP signaling. Our data furthermore demonstrate interaction between PPARa and STAT transcription factors in PPARa-mediated transcriptional repression, and suggest interaction between PPARa and TBP, and PPARa and C/EBPa in PPARa-mediated transcriptional activation. Overall, our analysis leads to important new insights into the mechanisms and impact of transcriptional regulation by PPARa in human liver and highlight the importance of cross-talk with other transcription factors.