REST is a major negative regulator of endocrine differentiation during pancreas organogenesis

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. This research was supported by Ministerio de Ciencia, Innovación y Universidades (SAF2015-73226-JIN [Agencia Estatal de Investigación {AEI}/European Regional Development Fund, European Union {UE}] and RYC-2017-21950 [AEI/European Social Fund, UE] to M.R., and BFU2014-54284-R and RTI2018-095666-B-I00 to J.F.); the Medical Research Council (MR/L02036X/1), Wellcome Trust (WT101033), and European Research Council Advanced Grant (789055) (to J.F.); the Instituto de Salud Carlos III (CA18/00045 to J.L.M.); and a Spanish Ministry of Science, Innovation, and Universities (MCIU) fellowship (PTA2018-016371-I to M.M.). J.K.-C.'s and F.P.'s research was supported by L'Agence Nationale de la Recherche (ANR) grants, L'Institut Européen de Génomique du Diabète (EGID), ANR-10-LABX-0046, a French state fund managed by ANR under the frame program Investissements d'Avenir (I-SITE ULNE/ANR-16-IDEX-0004 ULNE to F.P.), and the European Consortium for Islet Transplantation funded by the Juvenile Diabetes Research Foundation International. Work in the Centre for Genomic Regulation was supported by the Centres de Recerca de Catalunya (CERCA) Programme, Generalitat de Catalunya, and Centro de Excelencia Severo Ochoa (SEV-2015-0510). Work at Institut d'Investigació Biomèdica de Bellvitge was supported by the CERCA Programme and Generalitat de Catalunya