miRNAs control insulin content in pancreatic β-cells via downregulation of transcriptional repressors

• Published in: The EMBO journal 2011-03, Vol.30 (5), p.835-845
• Main Authors: Melkman-Zehavi, Tal, Oren, Roni, Kredo-Russo, Sharon, Shapira, Tirosh, Mandelbaum, Amitai D, Rivkin, Natalia, Nir, Tomer, Lennox, Kim A, Behlke, Mark A, Dor, Yuval, Hornstein, Eran
• Format: Article
• Language: English
• Subjects: Animals; Beta cells; Blotting, Western; Cell Differentiation; Cells, Cultured; DEAD-box RNA Helicases - physiology; diabetes; Dicer1; Down-Regulation; Endoribonucleases - physiology; Glucose Intolerance; Humans; Immunoenzyme Techniques; insulin; Insulin - genetics; Insulin - metabolism; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Integrases - metabolism; Luciferases - metabolism; Mice; Mice, Knockout; MicroRNAs - antagonists & inhibitors; MicroRNAs - physiology; miRNA; post-transcriptional; Repressor Proteins - genetics; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Ribonuclease III; RNA, Messenger - genetics; Transcription, Genetic
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2010.361

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. A pancreatic β‐cell‐specific knockout of Dicer with a diabetic phenotype reveals critical roles for specific miRNAs in the regulation of insulin expression.