Insulin Receptor Associates with Promoters Genome-wide and Regulates Gene Expression

• Published in: Cell 2019-04, Vol.177 (3), p.722-736.e22
• Main Authors: Hancock, Melissa L., Meyer, Rebecca C., Mistry, Meeta, Khetani, Radhika S., Wagschal, Alexandre, Shin, Taehwan, Ho Sui, Shannan J., Näär, Anders M., Flanagan, John G.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Chromatin - metabolism; coregulator host cell factor-1; Gene Expression Regulation - drug effects; gene promoter; Genome-Wide Association Study; HCFC1; Host Cell Factor C1 - antagonists & inhibitors; Host Cell Factor C1 - genetics; Host Cell Factor C1 - metabolism; Humans; INSR; Insulin - metabolism; Insulin - pharmacology; insulin receptor signaling; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; nuclear receptor tyrosine kinase; Promoter Regions, Genetic; Protein Binding; Protein Subunits - metabolism; Receptor, Insulin - chemistry; Receptor, Insulin - metabolism; RNA Interference; RNA polymerase II; RNA Polymerase II - metabolism; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; transcription factor
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.02.030

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. [Display omitted] •Cell-surface IR translocates to the nucleus and associates with promoters genome-wide•IR interaction with DNA is mediated by coregulator HCF-1 and transcription factors•IR associates with Pol II and regulates gene expression•Target genes are characteristic of insulin functions in physiology and disease Insulin receptor translocates from the cell surface to the nucleus, where it associates with transcriptional machinery at promoters, and regulates genes linked to insulin functions.