2158-P: GLIS3 Is Crucial for Maintenance of Neonatal ß Cells

The Krüpple-like zinc finger transcription factor, GLI-similar 3 (GLIS3), is critical for pancreatic β cell development and insulin production. Mutations and single nucleotide variants in the GLIS3 gene have been linked to the development of neonatal diabetes and increased risk of type 1 and 2 diabetes. Early during postnatal development pancreatic β cells proliferate and mature; however, little is known about the role of GLIS3 during this stage of β cell development. In this study, we examined the role of GLIS3 on gene expression in β cells during early mouse postnatal development. Immunohistochemistry, QRT-PCR, and transmission electron microscopy indicated that postnatal GLIS3KO islets still contain a large population of β cells that express PDX1, NKX6.1, and ISL-1; however, neonatal insulin production and insulin-secretory granules were greatly reduced in INS^lowPDX1⁺NKX6.1⁺ cells. Gene expression profiling by RNA-Seq with islets from WT and GLIS3KO mouse and identification of GLIS3 target genes by ChIP-Seq analysis showed that GLIS3 directly regulates the expression of a number of genes involved in β cell function and maturation, including Insulin1 and 2 (Ins1, Ins2), Solute Carrier Family 2 member 2 and 1(Slc2a2, Slc2a1), Activating Transcription Factor 4 and 6b (Atf4, Atf6b), and MAF BZIP Transcription Factor A (MafA), and as well as the expression of a number of metabolic genes. Our study indicates that GLIS3 plays a critical role in the maturation and maintenance of pancreatic β cells during early postnatal development by directly regulating genes with key β cell functions.