Reed Brian D, Charos Alexandra E, Szekely Anna M, Weissman Sherman M, Snyder Michael
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, USA.
PLoS Genet. 2008 Jul 25;4(7):e1000133. doi: 10.1371/journal.pgen.1000133.
The sterol regulatory element-binding protein (SREBP) family member SREBP1 is a critical transcriptional regulator of cholesterol and fatty acid metabolism and has been implicated in insulin resistance, diabetes, and other diet-related diseases. We globally identified the promoters occupied by SREBP1 and its binding partners NFY and SP1 in a human hepatocyte cell line using chromatin immunoprecipitation combined with genome tiling arrays (ChIP-chip). We find that SREBP1 occupies the promoters of 1,141 target genes involved in diverse biological pathways, including novel targets with roles in lipid metabolism and insulin signaling. We also identify a conserved SREBP1 DNA-binding motif in SREBP1 target promoters, and we demonstrate that many SREBP1 target genes are transcriptionally activated by treatment with insulin and glucose using gene expression microarrays. Finally, we show that SREBP1 cooperates extensively with NFY and SP1 throughout the genome and that unique combinations of these factors target distinct functional pathways. Our results provide insight into the regulatory circuitry in which SREBP1 and its network partners coordinate a complex transcriptional response in the liver with cues from the diet.
固醇调节元件结合蛋白（SREBP）家族成员SREBP1是胆固醇和脂肪酸代谢的关键转录调节因子，与胰岛素抵抗、糖尿病及其他饮食相关疾病有关。我们利用染色质免疫沉淀结合基因组平铺阵列（ChIP-chip），在人肝细胞系中全面鉴定了SREBP1及其结合伴侣NFY和SP1所占据的启动子。我们发现SREBP1占据了1141个参与多种生物学途径的靶基因的启动子，包括在脂质代谢和胰岛素信号传导中起作用的新靶标。我们还在SREBP1靶标启动子中鉴定出一个保守的SREBP1 DNA结合基序，并利用基因表达微阵列证明许多SREBP1靶基因通过胰岛素和葡萄糖处理被转录激活。最后，我们表明SREBP1在整个基因组中与NFY和SP1广泛合作，并且这些因子的独特组合靶向不同的功能途径。我们的结果为SREBP1及其网络伙伴在肝脏中根据饮食线索协调复杂转录反应的调控机制提供了见解。
