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首页> 外文期刊>Cell metabolism >Genome-wide Localization of SREBP-2 in Hepatic Chromatin Predicts a Role in Autophagy.
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Genome-wide Localization of SREBP-2 in Hepatic Chromatin Predicts a Role in Autophagy.

机译：SREBP-2全基因组在肝染色质中的定位预测自噬的作用。

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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.
机译：甾醇调节元件结合蛋白（SREBPs）是脂质代谢的关键转录调节因子。为了定义三种哺乳动物SREBP之间的功能差异，我们使用了全基因组ChIP-seq和同种型特异性抗体，并从选择的小鼠组织中选择了染色质，这些小鼠受到不同饮食条件的挑战，富含特定SREBPs。我们显示肝脏SREBP-2优先绑定到两个不同的基因近端基序。基因本体论（GO）分析表明，SREBP-2如预期的那样靶向脂质代谢过程，但细胞凋亡和自噬基因类别也得到了丰富。我们显示，SREBP-2在细胞固醇耗竭期间直接激活自噬基因，已知条件会诱导自噬和核SREBP-2水平。此外，营养物消耗期间的SREBP-2敲低减少了自噬小体靶向蛋白LC3的自噬小体形成和脂质滴缔合。因此，脂滴可被视为细胞胆固醇的第三种来源，其与固醇的合成和摄取也受SREBP-2的调节。

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