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

Young Kyo Seo, Tae Il Jeon, Hansook Kim Chong, Jacob Biesinger, Xiaohui Xie, Timothy F. Osborne

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)367-375
Number of pages9
JournalCell Metabolism
Volume13
Issue number4
DOIs
StatePublished - Apr 6 2011
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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