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

The transcription factor Peroxisome Proliferator-Activated Receptor (PPAR) is an important regulator of hepatic lipid metabolism. While PPAR is known to activate transcription of numerous genes, no comprehensive picture of PPAR binding to endogenous genes has yet been reported. To fill this gap, we performed ChIP-chip in combination with transcriptional profiling on HepG2 human hepatoma cells treated with the PPAR agonist GW7647. We found that GW7647 increased PPAR 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 PPAR, such as ACOX1, SULT2A1, ACADL, CD36, IGFBP1 and G0S2, showed GW7647-induced PPAR binding to their promoter. A GW7647-induced PPAR-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 PPAR and SREBP signaling. Our data furthermore demonstrate interaction between PPAR and STAT transcription factors in PPAR-mediated transcriptional repression, and suggest interaction between PPAR and TBP and C/EBP in PPAR-mediated transcriptional activation. Overall, our analysis leads to important new insights into the mechanisms and impact of transcriptional regulation by PPAR in human liver and highlight the importance of cross-talk with other transcription factors.

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van der Meer DL, Degenhardt T, Väisänen S, de Groot PJ, Heinäniemi M, de Vries SC, Müller M, Carlberg C, Kersten S