Dynamic DNA Methylation Changes ofTbx21andRorcduring Experimental Autoimmune Uveitis in Mice

Abstract

The key transcription factors of T helper cell subpopulations, including T-bet, GATA3, RORγt, and Foxp3 are involved in various autoimmune diseases. Whether methylation of these master transcription factors is associated with the development of experimental autoimmune uveitis (EAU) and the possible epigenetic regulatory mechanisms involved has however not yet been addressed. In our study, significant methylation changes in both Tbx21 and Rorc were observed in one CpG site in the retinas of EAU mice. Two CpG sites of Tbx21 and one CpG site of Rorc showed significant dynamic methylation changes in the RPE-choroid complex during EAU. The mRNA expressions of Tbx21 and Rorc in both the retinas and RPE-choroid complexes correlated with the methylation changes at the various time points during EAU development. The methylation changes were associated with the production of the Th1/Th17 cells' signature cytokines, IFN-γ and IL-17. Dynamic changes in mRNA expression of DNA methyltransferases (DNMT1) were also noted, which may be related to the observed methylation changes of these genes. The present study provides evidence that DNA methylation of Tbx21 and Rorc may be associated with the development of EAU. DNMT1 activation may have an important effect on regulating DNA methylation dynamics.

Influence of gut microbiota on eye diseases: an overview

“…The transcription factors Tbx21 and Rorc are known to be the main regulators of the differentiation of lymphocytes into T helper and T reg cells [ 22 , 23 ]. Hypomethylation of DNA factors discovered in the retinas and retinal pigment epithelium (RPE)–choroidal tissues of EAU mice was associated with an increased production of Th1/Th17-specific cytokines [interferon (IFN)-γ and interleukin (IL)-17] [ 24 ]. Additionally, miRNA-223 upregulation was also detected in this model, which was capable of promoting inflammation through the activation of T cells and myeloid dendritic cells.…”

A systematic review of gut microbiome and ocular inflammatory diseases: Are they associated?

“…Hypomethylation of these transcription factors due to reduction in the expression of DNA methyltransferase (DNMT1) was discovered in the retinas and RPE choroidal tissues of EAU mice and was associated with increased production of Th1/Th17 specific cytokines (IFNγ and IL-17). [ 48 ] But whether a similar mechanism operates in human uveitis patients is not known. It was also observed that miRNA-223 which is associated with microbiome dysbiosis and which promotes inflammation was upregulated in the EAU rat model.…”

Probiotic Supplementation Improved Acute Anterior Uveitis of 3-Year Duration: A Case Report

“…Therefore, it is crucial to identify the factors that trigger epigenetic changes leading to altered cellular function [ 6 ]. In a rat model of uveitis, the upregulation of micro-ribonucleic acid 223 (miRNA-223) was found to promote Th1/Th17 cytokines, including interferon (IFN)-g and interleukin (IL)-17 [ 7 ]. These authors linked the increased serum levels of miRNA-223 to microbiome dysbiosis.…”