REST is a major negative regulator of endocrine differentiation during pancreas organogenesis
- Meritxell Rovira1,2,3,4,
- Goutham Atla5,
- Miguel Angel Maestro5,6,
- Vane Grau5,6,
- Javier García-Hurtado5,6,
- Maria Maqueda7,
- Jose Luis Mosquera7,
- Yasuhiro Yamada8,
- Julie Kerr-Conte9,
- Francois Pattou9 and
- Jorge Ferrer5,6,10
- 1Department of Physiological Science, School of Medicine, Universitat de Barcelona (UB), L'Hospitalet de Llobregat, Barcelona 08907, Spain;
- 2Pancreas Regeneration: Pancreatic Progenitors and Their Niche Group, Regenerative Medicine Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain;
- 3Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia (P-CMR[C]), L'Hospitalet de Llobregat, Barcelona 08908, Spain;
- 4Center for Networked Biomedical Research on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid 28029, Spain;
- 5Regulatory Genomics and Diabetes, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona 08003, Spain;
- 6Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain;
- 7Bioinformatics Unit, Bellvitge Biomedical Research Institute, IDIBELL, L'Hospitalet del Llobregat, Barcelona 08908, Spain;
- 8Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan;
- 9Institute Pasteur Lille, University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU Lille), U1190, European Genomic Institute for Diabetes (EGID), Lille F-59000, France;
- 10Department of Metabolism, Digestion, and Reproduction, Section of Genetics and Genomics, Imperial College London, London W12 0NN, United Kingdom
- Corresponding authors: jorge.ferrer{at}crg.eu, mrovira{at}idibell.cat
Abstract
Multiple transcription factors have been shown to promote pancreatic β-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts and induced β-cell-specific genes in human adult duct-derived organoids. We also defined genomic sites that are bound and repressed by REST in the embryonic pancreas. Our findings show that REST-dependent inhibition ensures a balanced production of endocrine cells from embryonic pancreatic progenitors.
Keywords
- REST
- β cells
- bipotent progenitors
- endocrine differentiation
- pancreas
- pancreas development
- transcriptional repressors
Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.348501.121.
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Freely available online through the Genes & Development Open Access option.
- Received March 24, 2021.
- Accepted July 15, 2021.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
