Department of Pediatrics and Cell & Developmental Biology, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
Development. 2021 Mar 24;148(6):dev192401. doi: 10.1242/dev.192401.
Groucho-related genes (GRGs) are transcriptional co-repressors that are crucial for many developmental processes. Several essential pancreatic transcription factors are capable of interacting with GRGs; however, the role of GRG-mediated transcriptional repression in pancreas development is still not well understood. In this study, we used complex mouse genetics and transcriptomic analyses to determine that GRG3 is essential for β cell development, and in the absence of there is compensatory upregulation of double mutant mice have severe dysregulation of the pancreas gene program with ectopic expression of canonical liver genes and , a master regulator of the liver program. , an essential β cell transcription factor and predicted target of , becomes downregulated in mutants, resulting in reduced β cell proliferation, hyperglycemia, and early lethality. These findings uncover novel functions of GRG-mediated repression during pancreas development.
Groucho 相关基因 (GRGs) 是转录共抑制因子，对于许多发育过程至关重要。一些重要的胰腺转录因子能够与 GRGs 相互作用；然而，GRG 介导的转录抑制在胰腺发育中的作用仍不清楚。在这项研究中，我们使用复杂的小鼠遗传学和转录组分析来确定 GRG3 对于β细胞发育是必需的，并且在缺乏的情况下，会代偿性地上调 在双突变小鼠中，胰腺基因程序严重失调，经典的肝脏基因和 异位表达， 是肝脏程序的主要调节因子。 作为必需的β细胞转录因子和 的预测靶标，在 突变体中下调，导致β细胞增殖减少、高血糖和早期死亡。这些发现揭示了 GRG 介导的抑制在胰腺发育过程中的新功能。
