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Genome‐wide Localization of SREBP‐2 in Mouse Liver‐Chromatin by ChIP‐seq

Sterol regulatory element‐binding proteins (SREBPs) are a family of basic helix‐loop‐helix leucine zipper (bHLH‐LZ) transcription factors that regulate lipid homeostasis. SREBP‐1 and SREBP‐2 are mainly involved in fatty acid and cholesterol metabolism, respectively, but a comprehensive genome‐wide distribution of the two SREBPs has not been possible until now. We previously reported the location of SREBP‐1 binding sites in mouse liver. Here, we report global targets of SREBP‐2 in mouse liver using chromatin imunoprecipitation–high‐throughput DNA sequencing. Antisera to SREBP‐2 were used with liver chromatin from mice fed a chow diet supplemented with lovastatin plus ezitimibe for one week, which leads to a huge induction of hepatic SREBP‐2 nuclear protein levels. After massive parallel DNA sequencing, mapping these reads to the mouse reference genome identified about 1500 peaks of SREBP‐2 binding in FDR, 0.05 and p‐value 10‐7. These binding peaks show a striking enrichment in proximal promoter regions, with 45% located within 1 kb upstream of a transcription start site. Our preliminary analyses indicates SREBP‐2 bound not only to many well‐characterized SREBP‐2 target genes but to several other previously unknown targets in lipid and carbohydrate metabolism as well as many putative target genes in other diverse biological pathways. Our report should be useful for understanding the mechanistic flexibility that has evolved at the individual gene/promoter level to maintain metabolic homeostasis in response to shifting diet conditions.