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

Abstract

In addition to signaling through the classical tyrosine kinase pathway, recent studies indicate that insulin receptors (IRs) and insulinlike 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.

The Dark Side of Cell Signaling: Positive Roles for Negative Regulators

“…There is no doubt that these receptors are switched to active (or canonical) signaling states by their cognate ligands and signal according to their type—initiating both stimulatory signals and signals that terminate the initial ligand-induced stimulatory response. Far from being signaling-inactive in the absence of ligand, however, it is clear that the unoccupied dependence receptors promote proapoptotic responses or control expression of imprinted genes and miRNAs, and these effects are reversed—or switched “off”—by the cognate ligand (Boucher et al, 2014; Goldschneider and Mehlen, 2010). One key feature of most of the dependence receptors is that they are subject to cleavage by caspases in the absence of ligand, with the resulting fragments mediating proapoptotic signaling.…”

Imprinted genes in myeloid lineage commitment in normal and malignant hematopoiesis

“…129 According to Sharma et al 130 lung cancer stem cell chemoresistance was attributed to the upregulation of IGF1R and subsequent upregulation of the JARID1A demethylase, which in turn interacted with RB and HOX genes affecting tumor progression. Based on these findings and the data reported by Boucher et al, 13 a similar putative network/ loop comprising IGF1R-IGs-epigenetic machinery should be explored in LSCs chemoresistence.…”

“…According to such model loss of insulin receptor and Igf1r in mice induces a significant decrease in the expression of multiple IGs like Igf2, H19, Dlk1 and Cdkn1c regardless of the parent-of-origin expression status. 13 BIOLOGIC ASPECTS OF IGS Genomic imprinting has a role in regulating placental development and fetal growth, neonatal feeding, body temperature maintenance, metabolism regulation, infant and maternal behavior toward optimal maternal care, sleep regulation, adult neurogenesis, stem cell biology, and quiescence of the recently discovered but controversial, very small embryonic-like stem cells (VSELs). 1,14,15 VSELs are important as they have been considered the most primitive murine bone marrow (BM) residing cell stem cell population, sharing some characteristics with the long-term hematopoietic stem cells (HSCs).…”

Environmentally sensitive hotspots in the methylome of the early human embryo

“…Zink et al 23 were unable to demonstrate PofO allele-specific expression (PofO-ASE) in this region although others have found evidence of maternal imprinting of an intronic lncRNA at this gene in cancerous cells 43,44 . Interestingly, loss of IGF1 receptors gives rise to a major decrease in expression at multiple imprinted genes in mice suggesting a pathway by which IGF1R might regulate growth and metabolism during early development 45 . IGF1R signalling is implicated in fetal growth, glucose metabolism and cancer [46][47][48] , and DNAm differences at IGF1R have been observed in birthweight-discordant adult twins 49 .…”