Lopez-Noriega Livia, Callingham Rebecca, Martinez-Sánchez Aida, Nawaz Sameena, Pizza Grazia, Haberman Nejc, Cvetesic Nevena, Nguyen-Tu Marie-Sophie, Lenhard Boris, Marchetti Piero, Piemonti Lorenzo, de Koning Eelco, Shapiro A M James, Johnson Paul R, Leclerc Isabelle, Hastoy Benoit, Gauthier Benoit R, Pullen Timothy J, Rutter Guy A
Section of Cell Biology and Functional Genomics, Department of Medicine, Endocrinology and Metabolism, Imperial College London, London, UK.
Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
iScience. 2024 Dec 9;28(1):111518. doi: 10.1016/j.isci.2024.111518. eCollection 2025 Jan 17.
Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of beta cell function. Here, we show that an lncRNA-transcribed antisense to Pax6, annotated as Pax6os1/PAX6-AS1, was upregulated by high glucose concentrations in human as well as murine beta cell lines and islets. Elevated expression was also observed in islets from mice on a high-fat diet and patients with type 2 diabetes. Silencing / in MIN6 or EndoC-βH1 cells increased several beta cell signature genes' expression. Pax6os1/PAX6-AS1 was shown to bind to EIF3D, indicating a role in translation of specific mRNAs, as well as histones H3 and H4, suggesting a role in histone modifications. Important interspecies differences were found, with a stronger phenotype in humans. Only female null mice fed a high-fat diet showed slightly enhanced glucose clearance. In contrast, silencing in human islets enhanced glucose-stimulated insulin secretion and increased calcium dynamics, whereas overexpression of the lncRNA resulted in the opposite phenotype.
长链非编码RNA（lncRNAs）正逐渐成为β细胞功能的关键调节因子。在此，我们表明，一种转录方向与Pax6相反的lncRNA，注释为Pax6os1/PAX6-AS1，在人及小鼠β细胞系和胰岛中，会因高糖浓度而上调。在高脂饮食小鼠的胰岛以及2型糖尿病患者的胰岛中也观察到表达升高。在MIN6或EndoC-βH1细胞中沉默该lncRNA会增加几种β细胞特征基因的表达。研究表明，Pax6os1/PAX6-AS1与真核翻译起始因子3D（EIF3D）结合，表明其在特定mRNA的翻译中发挥作用，同时还与组蛋白H3和H4结合，提示其在组蛋白修饰中发挥作用。研究发现了重要的种间差异，在人类中表型更强。只有高脂饮食喂养的雌性基因敲除小鼠表现出葡萄糖清除率略有提高。相反，在人胰岛中沉默该lncRNA可增强葡萄糖刺激的胰岛素分泌并增加钙动力学，而该lncRNA的过表达则导致相反的表型。
