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

doi:10.1016/j.isci.2024.111518

Roles for the long non-coding RNA Pax6os1/ PAX6-AS1 in pancreatic beta cell function

iScience. 2024 Dec 9;28(1):111518. doi: 10.1016/j.isci.2024.111518. eCollection 2025 Jan 17.

Authors

Livia Lopez-Noriega¹, Rebecca Callingham¹, Aida Martinez-Sánchez¹, Sameena Nawaz², Grazia Pizza¹, Nejc Haberman^{3

4}, Nevena Cvetesic², Marie-Sophie Nguyen-Tu¹, Boris Lenhard^{3

4}, Piero Marchetti⁵, Lorenzo Piemonti^{6

7}, Eelco de Koning^{8

9}, A M James Shapiro¹⁰, Paul R Johnson¹¹, Isabelle Leclerc¹, Benoit Hastoy², Benoit R Gauthier^{12

13}, Timothy J Pullen^{1

14}, Guy A Rutter^{1

15

16

17}

Affiliations

¹ Section of Cell Biology and Functional Genomics, Department of Medicine, Endocrinology and Metabolism, Imperial College London, London, UK.
² Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³ Computational Regulatory Genomics, MRC Laboratory of Medical Sciences, London, UK.
⁴ Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
⁵ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
⁶ San Raffaele Diabetes Research Institute (SR-DRI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
⁷ Vita-Salute San Raffaele University, Milan, Italy.
⁸ Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands.
⁹ Hubrecht Institute, Utrecht, the Netherlands.
¹⁰ Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada.
¹¹ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
¹² Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain.
¹³ Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Madrid, Spain.
¹⁴ Department of Diabetes, King's College London, London, UK.
¹⁵ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
¹⁶ CR-CHUM, Université de Montréal, Montréal, QC, Canada.
¹⁷ Research Institute of McGill University Health Centre, Montréal, QC, Canada.

Abstract

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.

Keywords: Cell biology; Cellular physiology; Molecular biology.