Transcriptomic analyses of embryonic pancreata from pancreas-specific Groucho mutants

A large number of studies have identified and characterized the many transcription factors and cofactors that regulate pancreas organogenesis. Groucho-related genes/Transducin-like Enhancer of Split (Grgs/TLEs) are one such family of cofactors that act as transcriptional co-repressors and are critical 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 only partially characterized. In this study, we used phenotypic and transcriptomic analyses to determine that GRG3 is essential for β cell development, and in the absence of Grg3 there is compensatory upregulation of Grg4. In Grg3/4 double mutants, mice have severe dysregulation of the pancreas gene program with ectopic expression of liver genes and Foxa1, a master regulator of the liver program. Neurod1, an essential β cell transcription factor and predicted target of Foxa1, becomes downregulated in Grg3/4 mutants, resulting in a loss of β cell proliferation, hyperglycemia, and early lethality. These findings uncover a novel function of GRG-mediated repression in pancreas development. e18.5 pancreas RNA-seq from Pdx1:Cre, Pdx1:Cre; Grg and Pdx1:Cre; Grg3/4 embryos (n=3 for each genotype)