Groucho co-repressors in the regulation of pancreatic islet development

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Project Summary Loss of insulin-producing β cell number and function, the defining characteristics of Type 1 and Type 2 diabetes (T1D and T2D, respectively), affects over 30 million people in the United States. The cellular mechanisms that lead to this disease remain unknown, although significant research is currently ongoing to understand the development and function of β cells to ultimately advance our knowledge of the disease and generate effective treatments for diabetes. Much of the work in this field has described the transcription factors that are necessary for regulating gene expression during these processes. However, transcription factors do not act alone to regulate gene expression; other factors, such as co-activators and co-repressors, also interact with and influence transcription factor activity to allow activation or repression of target genes. One group of proteins that interact with transcription factors are the Groucho-related gene (GRG) family of co-repressors. GRGs do not bind directly to DNA – instead they are recruited to DNA by an array of transcription factors. GRGs promote repression of target genes by recruiting epigenetic modifiers, such as HDACs, to silence gene expression. Recent studies have shown that the mechanism of GRG-mediated gene regulation may not be this straight-forward and that the function of GRGs differ in cell-to-cell and context-dependent manners. GRGs have been shown to interact with critical pancreas transcription factors in the pancreas and in other biological systems. The interaction of GRG3 with NKX2.2, a pancreas transcription factor, is necessary for β cell development by repressing non-β cell programs. GRGs also interact with other pancreas transcription factors, such as NKX6.1 and PAX6 in other contexts, suggesting that GRGs may modulate activity of multiple transcription factors during β cell development and function. Preliminary data demonstrates that loss of Grg3 in the pancreas results in hyperglycemia and alterations in endocrine cell numbers in mice. Together, these data indicate that GRG3 is important in β cell development and function, although the molecular mechanism of GRGs in these processes is not fully understood. In this proposal, I will elucidate the mechanism of GRG transcriptional activity in the regulation of β cell identity and function using in vivo and in vitro approaches.