Nutrition, Metabolism and Genomics group, Division of Human Nutrition, Wageningen University, Bomenweg 2, NL-6703 HD Wageningen, The Netherlands.
Nucleic Acids Res. 2010 May;38(9):2839-50. doi: 10.1093/nar/gkq012. Epub 2010 Jan 27.
The transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) is an important regulator of hepatic lipid metabolism. While PPARalpha is known to activate transcription of numerous genes, no comprehensive picture of PPARalpha 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 PPARalpha agonist GW7647. We found that GW7647 increased PPARalpha 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 PPARalpha, such as ACOX1, SULT2A1, ACADL, CD36, IGFBP1 and G0S2, showed GW7647-induced PPARalpha binding to their promoter. A GW7647-induced PPARalpha-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 PPARalpha and SREBP signaling. Our data furthermore demonstrate interaction between PPARalpha and STAT transcription factors in PPARalpha-mediated transcriptional repression, and suggest interaction between PPARalpha and TBP, and PPARalpha and C/EBPalpha in PPARalpha-mediated transcriptional activation. Overall, our analysis leads to important new insights into the mechanisms and impact of transcriptional regulation by PPARalpha in human liver and highlight the importance of cross-talk with other transcription factors.
转录因子过氧化物酶体增殖物激活受体α（PPARα）是肝脏脂质代谢的重要调节因子。虽然已知 PPARα激活许多基因的转录，但尚未报道 PPARα 与内源性基因结合的综合情况。为了填补这一空白，我们在经 PPARα 激动剂 GW7647 处理的 HepG2 人肝癌细胞中进行了染色质免疫沉淀（ChIP）-芯片与转录谱分析。我们发现 GW7647 增加了 PPARα 与 4220 个结合区域的结合。GW7647 诱导的结合区域在转录起始位点周围存在偏向性，并且大多数包含预测的 PPAR 结合基序。几个已知受 PPARα 调节的基因，如 ACOX1、SULT2A1、ACADL、CD36、IGFBP1 和 G0S2，显示 GW7647 诱导其启动子上的 PPARα 结合。GW7647 诱导的 PPARα 结合区域也被分配到 SREBP 靶标 HMGCS1、HMGCR、FDFT1、SC4MOL 和 LPIN1，它们的表达受 GW7647 诱导，表明 PPARα 和 SREBP 信号之间存在串扰。我们的数据还证明了 PPARα 在 PPARα 介导的转录抑制中的 STAT 转录因子之间的相互作用，并表明 PPARα 在 PPARα 介导的转录激活中与 TBP、PPARα 和 C/EBPα 之间的相互作用。总体而言，我们的分析为 PPARα 在人类肝脏中的转录调节机制和影响提供了重要的新见解，并强调了与其他转录因子相互作用的重要性。
