Abstract
Transcription factor 19 (TCF19) is a gene associated with 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 and human islets 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 RNA-seq 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 viral responses, 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 can provide potential targets for improving β-cell survival.
Highlights
The pancreatic β-cells are endocrine cells whose primary role is to synthesize and secrete insulin
Based on our original studies on Tcf19, we concluded that Tcf19 was necessary for normal β-cell proliferation, as Tcf19 knockdown led to impaired cell cycle progression, reduced 3H-thymidine incorporation, and G1/S cell cycle arrest [21]
Inflammation is a pathophysiological state associated with both T1DM and T2DM
Summary
The pancreatic β-cells are endocrine cells whose primary role is to synthesize and secrete insulin. The pancreatic β-cell is susceptible to many different stressors including oxidative stress, endoplasmic reticulum (ER) stress, and inflammation [1,2] These stressors are exacerbated in patients with obesity, insulin resistance, and diabetes [3,4,5]. Hyperglycemia, as well as metabolic abnormalities associated with diabetes can lead to oxidative stress, resulting in increased intracellular reactive oxygen species (ROS) that contribute to β-cell dysfunction [11,12]. DNA damage in islets elicited by the β-cell toxin, streptozotocin (STZ), causes an elevation of proinflammatory cytokines [14] This inflammatory response is attenuated after inactivation of the master DNA repair gene, ataxia telangiectasia mutated (ATM) [14]. A better understanding of the intersection between these processes will provide potential regulatory targets to reduce and resolve DNA damage and inflammatory stress on the β-cell that may serve to help maintain adequate β-cell mass and function in diabetes
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