The long non-coding RNA Pax6os1/PAX6-AS1 modulates pancreatic β-cell identity and function

Abstract

Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of β-cell development and function. Here, we investigate roles for an antisense lncRNA expressed from the Pax6 locus (annotated as Pax6os1 in mice and PAX6-AS1 in humans) in β-cell function. Pax6os1/PAX6-AS1 expression was increased in islets from mice fed a high fat diet and in those from patients with type 2 diabetes. Silencing or deletion of Pax6os1/PAX6-AS1 in MIN6 and EndoC-βH1cells, respectively, upregulated β-cell signature genes, including Insulin. Moreover, shRNA-mediated silencing of PAX6-AS1 in human islets increased insulin mRNA, enhanced glucose-stimulated insulin secretion and calcium dynamics, while overexpressing the lncRNA reduced insulin expression and secretion. Together, our results suggest that increased expression of PAX6-AS1 at high glucose levels may contribute to β-cell dedifferentiation and failure in some forms of type 2 diabetes. Thus, targeting PAX6-AS1 may provide a promising strategy to enhance insulin secretion and improve glucose homeostasis in this disease.