Genome-wide Localization of SREBP-2 in Hepatic Chromatin Predicts a Role in Autophagy

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 diff...

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Veröffentlicht in:Cell metabolism 2011-04, Vol.13 (4), p.367-375
Hauptverfasser: Seo, Young-Kyo, Jeon, Tae-Il, Chong, Hansook Kim, Biesinger, Jacob, Xie, Xiaohui, Osborne, Timothy F.
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Sprache:eng
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Zusammenfassung: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. [Display omitted] ▴ SREBP-2 binds preferentially within 2 kb of the 5′ end of target genes ▴ SREBP-2 activates genes involved in autophagy during nutrient depletion ▴ Reduction of SREBP-2 leads to a decrease in autophagasome-lipid droplet association ▴ Autophagy and lipid regulation are linked in an adaptive mechanism to low nutrients
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2011.03.005