title: Genome-wide localization of SREBP-2 in hepatic chromatin predicts a role in autophagy.
abstract: Sterol regulatory element-binding proteins (SREBPs) are key transcriptional regulators of lipid metabolism. To define functional differences between the three mammalian SREBPs we used genome-wide ChIP-seq with isoform-specific antibodies and chromatin from select tissues of mice challenged with different dietary conditions that enrich for specific SREBPs. We show that hepatic SREBP-2 binds preferentially to two different gene-proximal motifs. A Gene Ontology (GO) analysis suggests SREBP-2 targets lipid metabolic processes as expected, but apoptosis and autophagy gene categories were also enriched. We show that SREBP-2 directly activates autophagy genes during cell-sterol depletion, conditions known to induce both autophagy and nuclear SREBP-2 levels. Additionally, SREBP-2 knockdown during nutrient depletion decreased autophagosome formation and lipid droplet association of the autophagosome targeting protein LC3. Thus, the lipid droplet could be viewed as a third source of cellular cholesterol, which along with sterol synthesis and uptake, is also regulated by SREBP-2.
authors: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.
authors: Young-Kyo
authors: YK
authors: Seo
authors: Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors: Tae-Il
authors: TI
authors: Jeon
authors: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA; Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, CA 92697, USA.
authors: Hansook Kim
authors: HK
authors: Chong
authors: Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, CA 92697, USA; Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA.
authors: Jacob
authors: J
authors: Biesinger
authors: Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, CA 92697, USA; Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA.
authors: Xiaohui
authors: X
authors: Xie
authors: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA; Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA. Electronic address: tosborne@sanfordburnham.org.
authors: Timothy F
authors: TF
authors: Osborne
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000032:analysis* / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D051782:Sterol Regulatory Element Binding Protein 2