University of Lille, Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, European Genomic Institute for Diabetes, U1011, Lille F-59045, France.
University of Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle, UMR 8576, Villeneuve d'Ascq F-59655, France.
Proc Natl Acad Sci U S A. 2018 Nov 20;115(47):E11033-E11042. doi: 10.1073/pnas.1805397115. Epub 2018 Nov 5.
The nuclear receptor REV-ERBα integrates the circadian clock with hepatic glucose and lipid metabolism by nucleating transcriptional comodulators at genomic regulatory regions. An interactomic approach identified O-GlcNAc transferase (OGT) as a REV-ERBα-interacting protein. By shielding cytoplasmic OGT from proteasomal degradation and favoring OGT activity in the nucleus, REV-ERBα cyclically increased O-GlcNAcylation of multiple cytoplasmic and nuclear proteins as a function of its rhythmically regulated expression, while REV-ERBα ligands mostly affected cytoplasmic OGT activity. We illustrate this finding by showing that REV-ERBα controls OGT-dependent activities of the cytoplasmic protein kinase AKT, an essential relay in insulin signaling, and of ten-of-eleven translocation (TET) enzymes in the nucleus. AKT phosphorylation was inversely correlated to REV-ERBα expression. REV-ERBα enhanced TET activity and DNA hydroxymethylated cytosine (5hmC) levels in the vicinity of REV-ERBα genomic binding sites. As an example, we show that the REV-ERBα/OGT complex modulates gene expression throughout the fasting/feeding periods by first repressing AKT phosphorylation and by epigenomically priming the promoter for a further rapid response to insulin. Conclusion: REV-ERBα regulates cytoplasmic and nuclear OGT-controlled processes that integrate at the hepatic locus to control basal and insulin-induced expression of the temporally and nutritionally regulated lipogenic transcript.
核受体 REV-ERBα 通过在基因组调节区域形成转录共调节剂，将生物钟与肝葡萄糖和脂质代谢联系起来。一种互作组学方法鉴定出 O-GlcNAc 转移酶 (OGT) 是 REV-ERBα 的相互作用蛋白。通过将细胞质中的 OGT 从蛋白酶体降解中屏蔽出来，并促进核内的 OGT 活性，REV-ERBα 周期性地增加多种细胞质和核蛋白的 O-GlcNAc 化，作为其节律性调节表达的功能，而 REV-ERBα 配体主要影响细胞质 OGT 活性。我们通过表明 REV-ERBα 控制细胞质蛋白激酶 AKT 的 OGT 依赖性活性来阐明这一发现，AKT 是胰岛素信号传递中的一个重要中继，以及核中的 ten-of-eleven 易位 (TET) 酶。AKT 磷酸化与 REV-ERBα 表达呈负相关。REV-ERBα 增强了 TET 活性和靠近 REV-ERBα 基因组结合位点的 DNA 羟甲基化胞嘧啶 (5hmC) 水平。例如，我们表明 REV-ERBα/OGT 复合物通过首先抑制 AKT 磷酸化，并通过表观遗传方式为胰岛素的快速反应启动 基因启动子，来调节禁食/进食期间的基因表达。结论：REV-ERBα 调节细胞质和核 OGT 控制的过程，这些过程在肝脏 基因座处整合，以控制基础和胰岛素诱导的时空和营养调节的脂肪生成 转录本的表达。
