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

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.

Keywords: HCFC1; INSR; RNA polymerase II; coregulator host cell factor-1; gene promoter; insulin receptor signaling; nuclear receptor tyrosine kinase; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Gene Expression Regulation* / drug effects
  • Genome-Wide Association Study*
  • Host Cell Factor C1 / antagonists & inhibitors
  • Host Cell Factor C1 / genetics
  • Host Cell Factor C1 / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin / pharmacology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Subunits / metabolism
  • RNA Interference
  • RNA Polymerase II / metabolism
  • RNA, Small Interfering / metabolism
  • Receptor, Insulin / chemistry
  • Receptor, Insulin / metabolism*
  • Signal Transduction / drug effects


  • Chromatin
  • Host Cell Factor C1
  • Insulin
  • Protein Subunits
  • RNA, Small Interfering
  • Receptor, Insulin
  • RNA Polymerase II