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REST is a major negative regulator of endocrine differentiation during pancreas organogenesis Rovira, Meritxell Atla, Goutham Maestro, Miguel Angel Grau, Vanessa García Hurtado, Javier Ferrer, Jorge Maqueda, Maria Mosquera Mayo, José Luís Kerr-Conte, Julie Pattou, Francois Pàncrees Organogènesi Biologia molecular Pancreas Organogenesis Molecular biology Understanding genomic regulatory mechanisms of pancreas differentiation is relevant to the pathophysiology of diabetes mellitus, and to the development of replacement therapies. Numerous transcription factors promote β cell differentiation, although less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrine gene programs in the embryonic pancreas. However, pancreatic Rest knock-out mice failed to show increased 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 now observe a marked increase in the formation of pancreatic endocrine cells. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts, and induced β-cell specific genes in human adult ductderived organoids. Finally, we define REST genomic programs that suppress pancreatic endocrine differentiation. These results establish a crucial role of REST as a negative regulator of pancreatic endocrine differentiation. 2021-09-21T11:02:58Z 2021-09-21T11:02:58Z 2021-08 2021-09-21T11:02:58Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 0890-9369 https://hdl.handle.net/2445/180146 713535 34385258 eng Reproducció del document publicat a: https://doi.org/10.1101/gad.348501.121 Genes & Development, 2021, vol. 35, num. 17-18, p. 1229-1243 https://doi.org/10.1101/gad.348501.121 info:eu-repo/grantAgreement/EC/H2020/789055/EU//DecodeDiabetes cc by (c) Rovira, Meritxell et al., 2021 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess 15 p. application/pdf Cold Spring Harbor Laboratory Press Articles publicats en revistes (Ciències Fisiològiques)