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, pa...

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Bibliographic Details
Published in:Genes & development 2021-09, Vol.35 (17-18), p.1229-1242
Main Authors: Rovira, Meritxell, Atla, Goutham, Maestro, Miguel Angel, Grau, Vane, García-Hurtado, Javier, Maqueda, Maria, Mosquera, Jose Luis, Yamada, Yasuhiro, Kerr-Conte, Julie, Pattou, Francois, Ferrer, Jorge
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - genetics
Gene Expression Regulation, Developmental
Life Sciences
Mice
Organogenesis - genetics
Pancreas
Research Paper
Zebrafish - genetics
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Summary: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 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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.348501.121