A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes

Sarah Merz; Valérie Senée; Anne Philippi; Franz Oswald; Mina Shaigan; Marita Führer; Cosima Drewes; Chantal Allgöwer; Rupert Öllinger; Martin Heni; Anne Boland; Jean-François Deleuze; Franziska Birkhofer; Eduardo G Gusmao; Martin Wagner; Meike Hohwieler; Markus Breunig; Roland Rad; Reiner Siebert; David Alexander Christian Messerer; Ivan G Costa; Fernando Alvarez; Cécile Julier; Alexander Kleger; Sandra Heller

doi:10.1016/j.celrep.2024.114853

A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes

Cell Rep. 2024 Oct 19;43(11):114853. doi: 10.1016/j.celrep.2024.114853. Online ahead of print.

Authors

Sarah Merz¹, Valérie Senée², Anne Philippi², Franz Oswald³, Mina Shaigan⁴, Marita Führer⁵, Cosima Drewes⁶, Chantal Allgöwer¹, Rupert Öllinger⁷, Martin Heni⁸, Anne Boland⁹, Jean-François Deleuze⁹, Franziska Birkhofer¹, Eduardo G Gusmao¹⁰, Martin Wagner³, Meike Hohwieler¹, Markus Breunig¹, Roland Rad⁷, Reiner Siebert⁶, David Alexander Christian Messerer¹¹, Ivan G Costa⁴, Fernando Alvarez¹², Cécile Julier¹³, Alexander Kleger¹⁴, Sandra Heller¹⁵

Affiliations

¹ Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany.
² Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France.
³ Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany.
⁴ Institute for Computational Genomics, RWTH Aachen University Medical School, Aachen, Germany.
⁵ Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and University Hospital Ulm, Ulm, Germany.
⁶ Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm, Germany.
⁷ Institute of Molecular Oncology and Functional Genomics, Center for Translational Cancer Research and Department of Medicine II, School of Medicine, Technical University of Munich, Munich, Germany.
⁸ Division of Endocrinology and Diabetology, Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany; Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany.
⁹ Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France.
¹⁰ Centre of Informatics, Federal University of Pernambuco, Recife, Brazil.
¹¹ Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and University Hospital Ulm, Ulm, Germany; Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany.
¹² Division of Gastroenterology, Hepatology & Nutrition, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada.
¹³ Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France. Electronic address: [email protected].
¹⁴ Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany; Division of Interdisciplinary Pancreatology, Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany; Core Facility Organoids, Ulm University, Ulm, Germany. Electronic address: [email protected].
¹⁵ Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany. Electronic address: [email protected].

PMID: 39427318
DOI: 10.1016/j.celrep.2024.114853

Abstract

In a patient with permanent neonatal syndromic diabetes clinically similar to cases with ONECUT1 biallelic mutations, we identified a disease-causing deletion located upstream of ONECUT1. Through genetic, genomic, and functional studies, we identified a crucial regulatory region acting as an enhancer of ONECUT1 specifically during pancreatic development. This enhancer region contains a low-frequency variant showing a strong association with type 2 diabetes and other glycemic traits, thus extending the contribution of this region to common forms of diabetes. Clinical relevance is provided by experimentally tailored therapy options for patients carrying ONECUT1 coding or regulatory mutations.

Keywords: CP: Developmental biology; CP: Metabolism; ONECUT1; cis-regulatory enhancer; human embryonic stem cells; lncRNA; monogenic diabetes; neonatal diabetes; pancreas differentiation; stem cell islets; type 2 diabetes.