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

Rovira Clusellas, Meritxell; Atla, Goutham; Maestro, Miguel Ángel; Grau, Vanessa; García-Hurtado, Javier; Maqueda, Maria; Mosquera, Jose Luis; Yamada, Yasuhiro; Kerr-Conte, Julie; Pattou, Francois; Ferrer, Jorge

doi:http://dx.doi.org/10.1101/gad.348501.121

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

License

Citation

Rovira M, Atla G, Maestro MA, Grau V, García-Hurtado, J Maqueda M et al. REST is a major negative regulator of endocrine differentiation during pancreas organogenesis. Genes Dev. 2021 Sep 1;35(17-18):1229-1242. DOI: 10.1101/gad.348501.121

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.