Genome-wide localization of SREBP-2 in hepatic chromatin predicts a role in autophagy.
Cell Metab, 2011/4/06;13(4):367-375.
Seo YK[1], Jeon TI[2], Chong HK[3], Biesinger J[4], Xie X[4], Osborne TF[5]
Affiliations
PMID: 21459322DOI: 10.1016/j.cmet.2011.03.005
Impact factor: 31.373
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.
MeSH terms
Animals; Autophagy; Cell Line; Chromatin; Chromatin Immunoprecipitation; Gene Expression Regulation; Genome; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Molecular Sequence Data; RNA Interference; RNA, Small Interfering; Sterol Regulatory Element Binding Protein 2
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