PT  - JOURNAL ARTICLE
AU  - Meritxell Rovira
AU  - Goutham Atla
AU  - Miguel Angel Maestro
AU  - Vane Grau
AU  - Javier García-Hurtado
AU  - Maria Maqueda
AU  - Jose Luis Mosquera
AU  - Julie Kerr-Conte
AU  - Francois Pattou
AU  - Jorge Ferrer
TI  - REST is a major negative regulator of endocrine differentiation during pancreas organogenesis
AID  - 10.1101/2021.03.17.435876
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.17.435876
4099  - http://biorxiv.org/content/early/2021/03/17/2021.03.17.435876.short
4100  - http://biorxiv.org/content/early/2021/03/17/2021.03.17.435876.full
AB  - 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 duct-derived 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.Competing Interest StatementThe authors have declared no competing interest.