Generation of a Novel Mouse Model to Study Pancreatic Beta-Cell Dedifferentiation

Abstract

Compromised β-cell identity triggered by metabolic stress has been revealed as a novel mechanism of insulin insufficiency in type 2 diabetes (T2D). Previous work from our group showed increased microRNA-7 (miR-7) expression in islets of mouse models of T2D and human islets exposed to an obesogenic environment. Murine β-cell-specific overexpression of miR-7 is sufficient to causes diabetes and is accompanied with decreased expression of β-cell identity markers, thus revealing miR-7 induction as a novel mechanism impairing β-cell identity. To address if insulin-producing cells can recover their function and identity in T2D, we engineered a novel mouse enabling us to temporally compromise the identity of β-cells through doxycycline-mediated miR-7 overexpression in vivo. We report that mutant mice exposed to doxycycline (Dox) displayed a severe diabetic phenotype characterized by hyperglycemia, glucose intolerance and reduced circulating insulin levels. Strikingly, four weeks after withdrawing Dox from the diet, we observed a complete normalization of glycemia, circulating insulin as well as the number of bihormonal cells in mutant mice. RNA seq analysis revealed that islets from miR-7-overexpressing mice exhibit a striking downregulation of β-cells identity markers and increased levels of α- and δ-cell specific genes. Interestingly, we measured upregulation of several genes involved in EMT, Inflammation and Stemness, pointing to a dedifferentiation of β-cells following induction of miR-7 expression. We provide novel evidence that miR-7 triggers an EMT process by repressing components of ATP-dependent chromatin remodelling complexes, altering nucleosome positioning at β-cell specific loci and ultimately causing dedifferentiation of β-cells. Together, our data reveal the mechanism underlying β-cell dedifferentiation by miR-7 and provide a proof of concept for the therapeutic efficacy of anti-miR-7 molecules in reversing β-cell dedifferentiation and improving β-cell function. Disclosure T.C.S. Mak: None. M. Latreille: None.