title: miRNAs control insulin content in pancreatic β-cells via downregulation of transcriptional repressors.
abstract: MicroRNAs (miRNAs) were shown to be important for pancreas development, yet their roles in differentiated β-cells remain unclear. Here, we show that miRNA inactivation in β-cells of adult mice results in a striking diabetic phenotype. While islet architecture is intact and differentiation markers are maintained, Dicer1-deficient β-cells show a dramatic decrease in insulin content and insulin mRNA. As a consequence of the change in insulin content, the animals become diabetic. We provide evidence for involvement of a set of miRNAs in regulating insulin synthesis. The specific knockdown of miR-24, miR-26, miR-182 or miR-148 in cultured β-cells or in isolated primary islets downregulates insulin promoter activity and insulin mRNA levels. Further, miRNA-dependent regulation of insulin expression is associated with upregulation of transcriptional repressors, including Bhlhe22 and Sox6. Thus, miRNAs in the adult pancreas act in a new network that reinforces insulin expression by reducing the expression of insulin transcriptional repressors.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Melkman-Zehavi
authors.forename: Roni
authors.initials: R
authors.lastname: Oren
authors.forename: Sharon
authors.initials: S
authors.lastname: Kredo-Russo
authors.forename: Tirosh
authors.initials: T
authors.lastname: Shapira
authors.forename: Amitai D
authors.initials: AD
authors.lastname: Mandelbaum
authors.forename: Natalia
authors.initials: N
authors.lastname: Rivkin
authors.forename: Tomer
authors.initials: T
authors.lastname: Nir
authors.forename: Kim A
authors.initials: KA
authors.lastname: Lennox
authors.forename: Mark A
authors.initials: MA
authors.lastname: Behlke
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.forename: Eran
authors.initials: E
authors.lastname: Hornstein
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D015536:Down-Regulation; D004722:Endoribonucleases / Q000502:physiology*; D018149:Glucose Intolerance; D006801:Humans; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000235:genetics* / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III; D014158:Transcription, Genetic
chemical_list: D007328:Insulin; D035683:MicroRNAs; D012333:RNA, Messenger; D012097:Repressor Proteins; D008156:Luciferases; C045073:Cre recombinase; D019426:Integrases; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases