Department of Physiological Science, School of Medicine, Universitat de Barcelona (UB), L'Hospitalet de Llobregat, Barcelona 08907, Spain.
Pancreas Regeneration: Pancreatic Progenitors and Their Niche Group, Regenerative Medicine Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.
Genes Dev. 2021 Sep 1;35(17-18):1229-1242. doi: 10.1101/gad.348501.121. Epub 2021 Aug 12.
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.
多种转录因子已被证明可促进胰腺β细胞的分化，但对于负调控因子的了解则较少。早期的表观基因组学研究表明，转录抑制因子 REST 可能是胚胎胰腺内分泌发生的抑制因子。然而，胰腺特异性敲除小鼠并未显示出内分泌细胞数量异常，这表明 REST 不是内分泌细胞分化的主要调节因子。使用一种可使 REST 深度失活的不同条件性等位基因，我们观察到胰腺内分泌细胞形成明显增加。REST 抑制也促进了斑马鱼和新生小鼠早期胰腺导管的内分泌发生，并在人成年导管来源的类器官中诱导了β细胞特异性基因。我们还定义了在胚胎胰腺中由 REST 结合和抑制的基因组位点。我们的研究结果表明，REST 依赖性抑制可确保胚胎胰腺祖细胞产生平衡数量的内分泌细胞。
