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Cell Metab. 2011 Apr 6;13(4):367-375. doi: 10.1016/j.cmet.2011.03.005.

Genome-wide localization of SREBP-2 in hepatic chromatin predicts a role in autophagy.

Author information

1
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.
2
Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
3
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.
4
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.
5
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.

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.

PMID:
21459322
PMCID:
PMC3086264
DOI:
10.1016/j.cmet.2011.03.005
[Indexed for MEDLINE]
Free PMC Article

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