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Identification of transcriptional targets during pancreatic growth after partial pancreatectomy and exendin-4 treatment

¹ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and the Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia
² Division of Endocrinology, Department of Pediatrics, The Children's Hospital of Philadelphia
³ Department of Genetics and the Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia
⁴ Penn Bioinformatics Core, University of Pennsylvania, Philadelphia, Pennsylvania

After partial pancreatectomy (Ppx), substantial regeneration of the endocrine and exocrine pancreatic compartments has been shown in adult rodents. Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor agonist that augments endocrine ß-cell mass by stimulating neogenesis, proliferation, and cell survival. After Ppx, treatment with Ex-4 ameliorates hyperglycemia by stimulating ß-cell mass recovery. We utilized a cDNA microarray approach to identify genes differentially regulated during pancreatic regeneration after Ppx and/or Ex-4 administration. The pancreatic remnant after Ppx showed a large number of differentially regulated genes. In contrast, Ex-4 treatment resulted in a smaller number of differentially regulated genes. Of note, a common subset of genes regulated by Ex-4 and after Ppx was identified, including three members of the mitogenic Reg gene family, Reg2, -3, and -3ß, as well as fragilis, a gene that maintains pluripotency during germ cell specification, and Serpin b1a, a member of an intracellular protease inhibitor family involved in cell survival. These observations were confirmed by real-time PCR. We determined that Reg3ß protein is also induced in the acinar pancreas after Ppx, suggesting a novel role for this factor in pancreatic growth or response to injury. Finally, comparison of transcription factor-binding sites present in the proximal promoters of these genes identified potential common transcription factors that may regulate these genes. Chromatin immunoprecipitation analyses confirmed Reg3 as a novel transcriptional target of Foxa2 (HNF3ß). Our data suggest molecular pathways that may regulate pancreatic growth and offer a unique set of candidate genes to target in the development of therapies aimed at improving pancreatic growth and function.

diabetes; ß-cell; pancreas; exenatide; glucagon-like peptide-1; islet; regeneration