title: 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 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.
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215;
authors.forename: Jeremie
authors.initials: J
authors.lastname: Boucher
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1TN, United Kingdom; and.
authors.forename: Marika
authors.initials: M
authors.lastname: Charalambous
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215; Energy Metabolism Laboratory, Department of Health Sciences and Technology, Swiss Federal Institute of Technology, 8092 Zurich, Switzerland.
authors.forename: Kim
authors.initials: K
authors.lastname: Zarse
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215;
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Mori
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215;
authors.forename: Andre
authors.initials: A
authors.lastname: Kleinridders
authors.affiliation: Energy Metabolism Laboratory, Department of Health Sciences and Technology, Swiss Federal Institute of Technology, 8092 Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Ristow
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1TN, United Kingdom; and.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215; c.ronald.kahn@joslin.harvard.edu.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling; D018392:Genomic Imprinting / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017526:Receptor, IGF Type 1 / Q000172:deficiency* / Q000235:genetics; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007328:Insulin; D035683:MicroRNAs; C012589:trichostatin A; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D001374:Azacitidine
keywords: developmental control; diabetes; transcriptional control