Insulin and insulin-like growth factor 1 receptors are required for normal expression of imprinted genes

Proc Natl Acad Sci U S A. 2014 Oct 7;111(40):14512-7. doi: 10.1073/pnas.1415475111. Epub 2014 Sep 22.

Abstract

In addition to signaling through the classical tyrosine kinase pathway, recent studies indicate that insulin receptors (IRs) and insulin-like growth factor 1 (IGF1) receptors (IGF1Rs) can emit signals in the unoccupied state through some yet-to-be-defined noncanonical pathways. Here we show that cells lacking both IRs and IGF1Rs exhibit a major decrease in expression of multiple imprinted genes and microRNAs, which is partially mimicked by inactivation of IR alone in mouse embryonic fibroblasts or in vivo in brown fat in mice. This down-regulation is accompanied by changes in DNA methylation of differentially methylated regions related to these loci. Different from a loss of imprinting pattern, loss of IR and IGF1R causes down-regulated expression of both maternally and paternally expressed imprinted genes and microRNAs, including neighboring reciprocally imprinted genes. Thus, the unoccupied IR and IGF1R generate previously unidentified signals that control expression of imprinted genes and miRNAs through transcriptional mechanisms that are distinct from classical imprinting control.

Keywords: developmental control; diabetes; transcriptional control.

Publication types

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

MeSH terms

  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, Brown / metabolism
  • Animals
  • Azacitidine / pharmacology
  • Cell Line, Transformed
  • Cells, Cultured
  • DNA Methylation / drug effects
  • DNA Methylation / genetics
  • Embryo, Mammalian / cytology
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression / drug effects
  • Gene Expression / genetics*
  • Gene Expression Profiling
  • Genomic Imprinting / genetics*
  • Histone Deacetylase Inhibitors / pharmacology
  • Hydroxamic Acids / pharmacology
  • Insulin / pharmacology
  • Insulin-Like Growth Factor I / pharmacology
  • Mice, Knockout
  • MicroRNAs / genetics
  • Oligonucleotide Array Sequence Analysis
  • Receptor, IGF Type 1 / deficiency*
  • Receptor, IGF Type 1 / genetics
  • Receptor, Insulin / deficiency*
  • Receptor, Insulin / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics

Substances

  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Insulin
  • MicroRNAs
  • trichostatin A
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Azacitidine