Elucidating the crosstalk between inflammation and DNA damage pathways in the pancreatic beta-cell through the diabetes susceptibility gene, TCF19

Abstract

AbstractTCF19 is a gene that is associated with both type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that TCF19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNAseq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in cell stress, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell, and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways may provide potential targets for β-cell survival.