Roles for the long non-coding RNA Pax6os1/PAX6-AS1 in pancreatic beta cell function
Livia Lopez-Noriega,
Rebecca Callingham,
Aida Martinez-Sánchez,
Sameena Nawaz,
Grazia Pizza,
Nejc Haberman,
Nevena Cvetesic,
Marie-Sophie Nguyen-Tu,
Boris Lenhard,
Piero Marchetti,
Lorenzo Piemonti,
Eelco de Koning,
A.M. James Shapiro,
Paul R. Johnson,
Isabelle Leclerc,
Benoit Hastoy,
Benoit R. Gauthier,
Timothy J. Pullen,
Guy A. Rutter
Affiliations
Livia Lopez-Noriega
Section of Cell Biology and Functional Genomics, Department of Medicine, Endocrinology and Metabolism, Imperial College London, London, UK
Rebecca Callingham
Section of Cell Biology and Functional Genomics, Department of Medicine, Endocrinology and Metabolism, Imperial College London, London, UK
Aida Martinez-Sánchez
Section of Cell Biology and Functional Genomics, Department of Medicine, Endocrinology and Metabolism, Imperial College London, London, UK
Sameena Nawaz
Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Grazia Pizza
Section of Cell Biology and Functional Genomics, Department of Medicine, Endocrinology and Metabolism, Imperial College London, London, UK
Nejc Haberman
Computational Regulatory Genomics, MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
Nevena Cvetesic
Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Marie-Sophie Nguyen-Tu
Section of Cell Biology and Functional Genomics, Department of Medicine, Endocrinology and Metabolism, Imperial College London, London, UK
Boris Lenhard
Computational Regulatory Genomics, MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
Piero Marchetti
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Lorenzo Piemonti
San Raffaele Diabetes Research Institute (SR–DRI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
Eelco de Koning
Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Hubrecht Institute, Utrecht, the Netherlands
A.M. James Shapiro
Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
Paul R. Johnson
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
Isabelle Leclerc
Section of Cell Biology and Functional Genomics, Department of Medicine, Endocrinology and Metabolism, Imperial College London, London, UK
Benoit Hastoy
Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Benoit R. Gauthier
Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain; Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Madrid, Spain
Timothy J. Pullen
Section of Cell Biology and Functional Genomics, Department of Medicine, Endocrinology and Metabolism, Imperial College London, London, UK; Department of Diabetes, King’s College London, London, UK; Corresponding author
Guy A. Rutter
Section of Cell Biology and Functional Genomics, Department of Medicine, Endocrinology and Metabolism, Imperial College London, London, UK; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; CR-CHUM, Université de Montréal, Montréal, QC, Canada; Research Institute of McGill University Health Centre, Montréal, QC, Canada; Corresponding author
Summary: 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 Pax6os1/PAX6-AS1 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 Pax6os1 null mice fed a high-fat diet showed slightly enhanced glucose clearance. In contrast, silencing PAX6-AS1 in human islets enhanced glucose-stimulated insulin secretion and increased calcium dynamics, whereas overexpression of the lncRNA resulted in the opposite phenotype.
