TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell

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.

Immunotherapeutic Value of Transcription Factor 19 (TCF19) Associated with Renal Clear Cell Carcinoma: A Comprehensive Analysis of 33 Human Cancer Cases

“…The genes associated with the TCF family regulate innate immunity and adaptive immunity [ 19 , 20 ]. It has been previously reported that TCF1 helps achieve a balance between the CD8+ T cells by regulating the internal IL-10 signaling pathway which in turn influences immunotherapy [ 21 ]. Macrophages, a substantial component of the innate immune system, are related to the antitumor immune response in various cancers.…”

Cell cycle regulation of the psoriasis associated gene CCHCR1 by transcription factor E2F1

“…Mechanistically, TCF19 was shown to recognize H3K4me3 [38] to control the expression of glucoseresponsive genes [38,39]. Similar to CCHCR1, TCF19 has been associated with diseases, including diabetes [40][41][42], HBV-related chronic hepatitis B, cirrhosis, hepatocellular carcinoma [43], non-small cell lung cancer [44], squamous cell carcinoma of the head and neck (SCCHN) [45] and colorectal cancer [46]. It is currently not known whether CCHCR1 and TCF19 act on the same cellular pathway.…”

What the BTBR/J mouse has taught us about diabetes and diabetic complications

“… 67 Knockdown of Tcf19 impairs β-cell proliferation whereas overexpression of Tcf19 leads to upregulation of cell stress response pathways, including those important in DNA damage repair. 66 , 68 Tcf19 expression, along with numerous other cell cycle genes, is induced by Nfatc2 in the islet. 69 DYRK1A inhibitors are an exciting new therapeutic target to promote β-cell proliferation, and a potential signaling pathway includes activation of NFATc2, leading to expression of Tcf19 and promotion of cell cycle gene expression.…”