GLIS3: A Critical Transcription Factor in Islet β-Cell Generation

Abstract

Understanding of pancreatic islet biology has greatly increased over the past few decades based in part on an increased understanding of the transcription factors that guide this process. One such transcription factor that has been increasingly tied to both β-cell development and the development of diabetes in humans is GLIS3. Genetic deletion of GLIS3 in mice and humans induces neonatal diabetes, while single nucleotide polymorphisms (SNPs) in GLIS3 have been associated with both Type 1 and Type 2 diabetes. As a significant progress has been made in understanding some of GLIS3’s roles in pancreas development and diabetes, we sought to compare current knowledge on GLIS3 within the pancreas to that of other islet enriched transcription factors. While GLIS3 appears to regulate similar genes and pathways to other transcription factors, its unique roles in β-cell development and maturation make it a key target for future studies and therapy.

circGlis3 promotes β-cell dysfunction by binding to heterogeneous nuclear ribonucleoprotein F and encoding Glis3-348aa protein

“…GLIS3 has been shown to directly regulate the transcription of targeted genes in β cells, including Ins2 , Ngn3, and Ccnd2 . 36 , 39 Of note, we found that the expression levels of Ins2 , Ngn3, and Ccnd2 were reduced by overexpressing circGlis3 in MIN6 cells and islets ( Figure S6 G and S6H). Given that Glis3-348aa bound to the C-terminal TAD of GLIS3 protein, we then wondered whether the transcriptional activity of GLIS3 was affected by Glis3-348aa.…”

“…GLIS3 protein, which is encoded by the Glis3 gene, is a transcription factor responsible for β-cell differentiation and insulin secretion. 36 The colocalization of Glis3-348aa and GLIS3 was observed in the nucleus of MIN6 cells ( Figure 6 A), and thus we wondered whether there was an interaction between Glis3-348aa and GLIS3 protein. Co-IP assays with anti-Glis3-348aa antibody showed that Glis3-348aa could interact with GLIS3 protein in MIN6 cells and mouse islets ( Figures 6 B and S6 B).…”

Post-Translational Modifications and Diabetes

“…Gli-similar 3 (Glis3), a transcription factor, is critical in b-cell development and proliferation, as well as the regulation of insulin gene expression [ 96 , 97 ]. Several single-nucleotide polymorphisms (SNPs) in Glis3 have been closely associated with T2D [ 98 ].…”

Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

“…The genetic pathways involved in different stages of the disease are highly divergent, and genetics is currently the only tool capable of detecting those at risk before the development of islet autoimmunity [75]. More and more genetic-based evidence points to the predisposition at the β-cell level, with risk variants affecting the susceptibility to pro-apoptotic stimuli and influencing β-cell phenotypes [50,57,76]. New in-depth analyses of the potential role of genetic variants in the progression from islet autoimmunity to clinical T1D at the genome-wide level using next-generation sequencing identified several novel risk genes associated with T1D.…”