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Review
. 2024 Mar 6:15:1289492.
doi: 10.3389/fimmu.2024.1289492. eCollection 2024.

Functional significance of DNA methylation: epigenetic insights into Sjögren's syndrome

Yanqing Wang #  1 , Farooq Riaz #  2 , Wei Wang #  3 , Jincheng Pu  1 , Yuanyuan Liang  1 , Zhenzhen Wu  1 , Shengnan Pan  1 , Jiamin Song  1 , Lufei Yang  1 , Youwei Zhang  1 , Huihong Wu  1 , Fang Han  1 , Jianping Tang  1 , Xuan Wang  1
Affiliations
Review

Functional significance of DNA methylation: epigenetic insights into Sjögren's syndrome

Yanqing Wang et al. Front Immunol. .

Abstract

Sjögren's syndrome (SjS) is a systemic, highly diverse, and chronic autoimmune disease with a significant global prevalence. It is a complex condition that requires careful management and monitoring. Recent research indicates that epigenetic mechanisms contribute to the pathophysiology of SjS by modulating gene expression and genome stability. DNA methylation, a form of epigenetic modification, is the fundamental mechanism that modifies the expression of various genes by modifying the transcriptional availability of regulatory regions within the genome. In general, adding a methyl group to DNA is linked with the inhibition of genes because it changes the chromatin structure. DNA methylation changes the fate of multiple immune cells, such as it leads to the transition of naïve lymphocytes to effector lymphocytes. A lack of central epigenetic enzymes frequently results in abnormal immune activation. Alterations in epigenetic modifications within immune cells or salivary gland epithelial cells are frequently detected during the pathogenesis of SjS, representing a robust association with autoimmune responses. The analysis of genome methylation is a beneficial tool for establishing connections between epigenetic changes within different cell types and their association with SjS. In various studies related to SjS, most differentially methylated regions are in the human leukocyte antigen (HLA) locus. Notably, the demethylation of various sites in the genome is often observed in SjS patients. The most strongly linked differentially methylated regions in SjS patients are found within genes regulated by type I interferon. This demethylation process is partly related to B-cell infiltration and disease progression. In addition, DNA demethylation of the runt-related transcription factor (RUNX1) gene, lymphotoxin-α (LTA), and myxovirus resistance protein A (MxA) is associated with SjS. It may assist the early diagnosis of SjS by serving as a potential biomarker. Therefore, this review offers a detailed insight into the function of DNA methylation in SjS and helps researchers to identify potential biomarkers in diagnosis, prognosis, and therapeutic targets.

Keywords: DNA methylation; Sjögrens syndrome (SjS); T cells; autoimmunity; demethylation; epigenetics; systemic autoimmune disease.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Graphical illustration of DNA methylation and its basic mechanism. The formation of novel DNA methylation patterns is modulated by methyltransferases (DNMTs). DNMTs aid in the formation of 5-methylcytosine from cytosine. This was followed by binding a methyl CpG-binding protein to methylated CpG sequences, which limits the ability of transcription factors (TFs) to reach this region, preventing the target genes’ transcription. Conversely, Ten Eleven Translocation (TET) proteins may initiate the demethylation and convert 5-methylcytosine to cytosine. This demethylation promotes the binding of TFs with non-methylated CpG to accelerate the expression of target genes.
Figure 2
Figure 2
Possible mechanism of DNA-methylation in the pathogenesis of SjS: Activation of toll-like receptors (TLRs) signaling, predominantly activated in the salivary gland epithelial cells (SGECs), produces autoantigens which enhances the production of immunocompetent cytokines and chemokines and cytokines. These lead to the apoptosis of SGECs, epithelial hypofunction and tissue damage. Autoantigens can be released from SGECs and presented to immune cells. CD4+ T cells differentiate into inflammatory Th1 and Th17 to participate in the tissue damage. Immunosuppressive Tregs inhibit the activity of inflammatory Th1 and Th17 cells. Methylation of RUNX1 activates the Th1 cells, whereas elevated RUNX1 binds with Foxp3 in Tregs, leading to transcriptional modification and enhancing its expression, which in turn inhibits the function of RUNX1. Meanwhile, LTA binds with TNF1 and TH=NF2 to activate JNK/NF-kB signaling, leading to inflammation. In addition, DNA methylation pattern of ADAMTS17, FMOD and ZAP70 is altered in a PKCδ/ERK/DNMT1-dependent manner. Increased B cells also activate plasma cells to produce antibodies against autoantigens. Meanwhile, DNA methylation of IFITM1, DTX3L and EPSTI1 activates the IFN signaling in monocytes to alleviate inflammation and tissue damage. Strikingly, inflammation-induced DNA methylation regions in major histocompatibility complex, IFN signaling induced JAK/STAT1 signaling, and altered levels of Gadd45α level and DNMT1 in SGECs also participates in the pathogenesis of SjS.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by the National Natural Science Foundation of China grants (81801601, 81671598), Natural Science Foundation of Shanghai grant (20ZR1451400), Science and technology commission of Shanghai (20Y11911600), the Shanghai SailingProgram (17YF1417200), Clinical research program of Tongji Hospital Tongji University (ITJZD1909, ITJQN2001). Shanghai Pujiang rheumatic youth cultivation program (SPROG1810).
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