Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Cell. 2019 Apr 18;177(3):722-736.e22. doi: 10.1016/j.cell.2019.02.030. Epub 2019 Apr 4.
Insulin receptor (IR) signaling is central to normal metabolic control and dysregulated in prevalent chronic diseases. IR binds insulin at the cell surface and transduces rapid signaling via cytoplasmic kinases. However, mechanisms mediating long-term effects of insulin remain unclear. Here, we show that IR associates with RNA polymerase II in the nucleus, with striking enrichment at promoters genome-wide. The target genes were highly enriched for insulin-related functions including lipid metabolism and protein synthesis and diseases including diabetes, neurodegeneration, and cancer. IR chromatin binding was increased by insulin and impaired in an insulin-resistant disease model. Promoter binding by IR was mediated by coregulator host cell factor-1 (HCF-1) and transcription factors, revealing an HCF-1-dependent pathway for gene regulation by insulin. These results show that IR interacts with transcriptional machinery at promoters and identify a pathway regulating genes linked to insulin's effects in physiology and disease.
胰岛素受体（IR）信号通路是正常代谢控制的核心，在常见的慢性疾病中失调。IR 在细胞表面与胰岛素结合，并通过细胞质激酶传递快速信号。然而，介导胰岛素长期作用的机制尚不清楚。在这里，我们显示 IR 在核内与 RNA 聚合酶 II 相关联，在全基因组范围内在启动子处有显著富集。靶基因高度富集与胰岛素相关的功能，包括脂质代谢和蛋白质合成，以及包括糖尿病、神经退行性疾病和癌症在内的疾病。胰岛素可增加 IR 的染色质结合，并在胰岛素抵抗疾病模型中受损。IR 通过辅助调节因子宿主细胞因子-1（HCF-1）和转录因子与启动子结合，揭示了胰岛素调节基因的 HCF-1 依赖性途径。这些结果表明，IR 在启动子处与转录机制相互作用，并确定了一条调节与胰岛素在生理和疾病中作用相关基因的途径。
