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

Significance Imprinted genes are normally selectively expressed, depending on the parent from whom the gene is inherited. These genes play important roles in control of growth and metabolism. We find that the loss of insulin and insulin-like growth factor 1 (IGF1) receptors in cells induces a major decrease in expression of multiple imprinted genes, regardless of whether they would be maternally or paternally expressed. This deregulation is associated with changes in methylation of DNA, but is not due to classical imprinting control. Our results demonstrate a previously unrecognized function of insulin and IGF1 receptors independent of these hormones and provide a new pathway by which insulin and IGF1 receptors may regulate growth and metabolism during early development and thereafter. 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.