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

Meritxell Rovira, Goutham Atla, Miguel Angel Maestro, Vane Grau, Javier García-Hurtado, Maria Maqueda, Jose Luis Mosquera, Yasuhiro Yamada, Julie Kerr-Conte, Francois Pattou,
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Published: 12 August 2021

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: transcription factors / differentiation / endocrine / ducts / regulator / pancreas / adult / endocrinogenesis / REST

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