Translocation of forkhead box O1 to the nuclear periphery induces histone modifications that regulate transcriptional repression of PCK1 in HepG2 cells
Translocation of forkhead box O1 to the nuclear periphery induces histone modifications that regulate transcriptional repression of PCK1 in HepG2 cells
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DOI：
10.1111/gtc.12226
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发表时间：
2015-04-01
期刊：
影响因子：
2.1
通讯作者：
Murata, Masayuki
中科院分区：
文献类型：
--
作者：
Arai, Tamaki;Kano, Fumi;Murata, Masayuki
叉头盒 O1 (FOXO1) 是胰岛素的重要靶点。人们普遍认为，胰岛素诱导的 Akt 对 FOXO1 进行磷酸化，导致其核排斥，并导致肝细胞中 FOXO1 介导的糖异生基因磷酸烯醇丙酮酸羧激酶 1 (PCK1) 的转录受到抑制。然而，已经积累了许多与该模型相矛盾的结果。在这里，我们提供了一种胰岛素依赖性抑制 FOXO1 介导的转录的新机制。我们展示了胰岛素诱导的内源性 Ser256 磷酸化 FOXO1 的易位，这对于调节 FOXO1 介导的转录从核斑点到核外围至关重要。 FOXO1 的这种胰岛素依赖性易位调节 PCK1 的转录抑制，同时形成 FOXO1-常染色组蛋白-赖氨酸 N-甲基转移酶 2 (EHMT2) 复合物和 PCK1 启动子区域的组蛋白修饰。值得注意的是，我们的结果表明 FOXO1 使用核孔蛋白 98kDa NUP98 进行这种转录调节。这些结果为各种 FOXO1 介导的转录调控和 FOXO1 介导的重要生物学途径提供了新的见解。
Forkhead box O1 (FOXO1) is an important target for insulin. It is widely accepted that insulin-induced phosphorylation of FOXO1 by Akt leads to its nuclear exclusion and results in the inhibition of FOXO1-mediated transcription of the gluconeogenic gene phosphoenolpyruvate carboxykinase 1 (PCK1) in hepatocytes. However, many results that contradict this model have accumulated. Here, we provide a new mechanism for insulin-dependent repression of FOXO1-mediated transcription. We showed insulin-induced translocation of endogenous Ser256-phosphorylated FOXO1, which is essential for regulation of FOXO1-mediated transcription, from nuclear speckles to the nuclear periphery. This insulin-dependent translocation of FOXO1 regulated transcriptional repression of PCK1 concomitant with the formation of the FOXO1-euchromatic histone-lysine N-methyltransferase2 (EHMT2) complex and histone modifications of the PCK1 promoter region. Notably, our results suggest that FOXO1 uses nucleoporin 98kDa NUP98 for this transcriptional regulation. These results provide a new insight into various FOXO1-mediated transcriptional regulation and FOXO1-mediated essential biological pathways.