Genome-wide occupancy of SREBP1 and its partners NFY and SP1 reveals novel functional roles and combinatorial regulation of distinct classes of genes.
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.
Reed
Brian D
BD
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, USA.
Charos
Alexandra E
AE
Szekely
Anna M
AM
Weissman
Sherman M
SM
Snyder
Michael
M
D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D015894:Genome, Human; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D023081:CCAAT-Binding Factor; D016329:Sp1 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1; C402244:nuclear factor Y