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

SummarySterol 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.

Graphical AbstractFigure optionsDownload high-quality image (262 K)Download as PowerPoint slideHighlights
► 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