The critical importance of epigenetics in autoimmune-related skin diseases

Abstract

Autoimmune-related skin diseases are a group of disorders with diverse etiology and pathophysiology involved in autoimmunity. Genetics and environmental factors may contribute to the development of these autoimmune disorders. Although the etiology and pathogenesis of these disorders are poorly understood, environmental variables that induce aberrant epigenetic regulations may provide some insights. Epigenetics is the study of heritable mechanisms that regulate gene expression without changing DNA sequences. The most important epigenetic mechanisms are DNA methylation, histone modification, and noncoding RNAs. In this review, we discuss the most recent findings regarding the function of epigenetic mechanisms in autoimmune-related skin disorders, including systemic lupus erythematosus, bullous skin diseases, psoriasis, and systemic sclerosis. These findings will expand our understanding and highlight the possible clinical applications of precision epigenetics approaches.

Keywords

epigenetics / autoimmune-related skin diseases / DNA methylation / histone modifications / noncoding RNAs

1 Introduction

The central dogma proposed that genetic information predominantly transfers from DNA to RNA during gene expression to make a functional product protein. This absolute theory has been debunked because of the influence of the environment on how genes are transcribed [1]. According to the human genome sequencing and analysis, an extremely complex regulatory mechanism is required to regulate gene expression inside the human body, resulting in the activation or inhibition of pathways or molecules that may contribute to health or illness [2]. Epigenetic processes partly account for this regulation. Epigenetics is the structural modification of chromosomal areas to record, signal, or maintain changed activity levels [3]. Since the word “epi” means “above,” epigenetics literally means “above genetics.” Over the past decades, the study of epigenetics has blossomed, exposing an astonishing level of complexity in the way genetic information is stored and retrieved in eukaryotes [4,5].

Autoimmunity is a pathological disease in which immune cells cannot recognize self-antigens; thus, they attack self-tissues and organs, causing inflammation and organ damage, including the skin [6,7]. As the body’s largest organ, the skin can be affected by overactivated immune cells and autoantibody production. The pathogenetic mechanisms related to autoimmunity in skin diseases remain poorly understood. However, these diseases are widely believed to result from the interaction of genetic susceptibility and environmental stimuli [8,9]. Although several associated risk loci have been found via genome-wide association analysis, the high prevalence of discordance in the occurrence of autoimmune diseases in homozygous twins cannot fully be explained by genetic factors [10,11]. A growing body of research has demonstrated that epigenetic modifications have a critical role in the onset and development of autoimmune-related skin diseases. Multiple forms of epigenetic modifications modulate gene expression. The three major features are DNA methylation, histone modifications, and noncoding RNAs (ncRNAs). These epigenetic modifications may substantially affect cell function, defining the phenotype of each cell. Therefore, this review summarizes the most important and current findings of epigenetic contributions to autoimmune diseases in dermatology, including systemic lupus erythematosus (SLE), bullous skin diseases, psoriasis, and systemic sclerosis (SSc) (Fig.1).

2 SLE

SLE is a multisystem autoimmune disorder affecting numerous organs, including the skin, kidneys, joints, and the central nervous system [11]. Over the past decades, numerous large-scale genetic association studies have discovered a considerable proportion of genetic heritability for SLE, demonstrating the impact of genetic susceptibility on disease development [12]. However, the incomplete concordance between monozygotic twins revealed that other nongenetic factors, such as epigenetics, hormones, and environmental factors, contribute to SLE development [13]. Moreover, environmental factors, including sunlight, diet, infection, and drugs, appear to result in these epigenetic differences. Dysregulated epigenetic alterations in immune cells play a crucial part in lupus pathophysiology. Moreover, discovered epigenetic abnormalities may serve as potential biomarkers or therapeutic targets (Tab.1).

2.1 DNA methylation

Numerous lines of evidence indicate that aberrant epigenetic regulations play a crucial role in SLE pathophysiology [4,5,14,15]. DNA methylation in a CpG island acts as an indicator of gene expression suppression. SLE patients with active lupus show global DNA hypomethylation in CD4⁺ T cells, which has been proved to play a critical role in SLE pathogenesis [15]. Autoimmune-related genes, including CD11a (ITGAL), CD70 (TNFSF7), perforin, and CD40 ligand (CD40L), show hypomethylation within regulatory sequences, thereby upregulating relevant genes found in SLE patients and positively correlated with disease activity [16–19]. Further study has revealed that the mechanism causing regulated CD11a and CD70 is caused by the decreased expression of transcription factor RFX1 in CD4⁺ T cells from lupus patients. RFX1 recruits corepressors DNA methyltransferase 1 (DNMT1) and deacetylase HDAC1 in the promoters of CD11a and CD70, thereby repressing their expression levels [20]. Another study indicated that CD70 gene upregulation and hypomethylation in SLE CD4⁺ T cells are caused by MBD4 downregulation [21]. Despite RFX1 and MBD4, the upstream pathway is linked to DNA-damage-inducible 45 α (Gadd45α), which promotes DNA demethylation in SLE CD4⁺ T cells and leads to lupus-like autoimmunity [22]. Hydroxymethylation, which reactivates suppressed genes, is also linked to SLE pathophysiology [23]. A comprehensive 5-hmC detection indicates that SLE CD4⁺ T cells exhibit elevated levels of total 5-hmC and hydroxymethylation in the promoter regions of a large number of genes. The transcription factor CCCTC-binding factor binds to the promoter regions of genes in CD4⁺ T cells, thereby proving its involvement in controlling the promoter hydroxymethylation of genes [24]. Moreover, studies have shown that interferon (IFN)-regulated genes in SLE have robust hypomethylation [25–27]. The IFN I pathway plays a pivotal role in SLE pathophysiology [28]. In the peripheral blood of SLE patients, two CpG sites located in the promoter region of IFI44L (IFN-induced protein 44-like) have substantial hypomethylation, distinguished as a highly sensitive and specific diagnostic biomarker for SLE [29]. Recent research has concentrated on the DNA methylation of Tfh cells and B cells. Bcl-6 binds to chromatin during Tfh cell programming; it is also connected to a reduction in 5-hmC, demonstrating that DNA methylation controls the Tfh cell development [30]. SLE CD4⁺ T cells have a high IL-21 concentration, which enhances hydroxymethyltransferase ten-eleven translocation 2 (TET2) enrichment in the promoter region of Bcl-6 (B cell lymphoma 6) and stimulates the Bcl-6 expression in SLE circulating Tfh cells [31]. A recent study has also discovered that IL-21 increases TET2 enrichment in the AIM2 promoter region, which promotes AIM2 expression [32]. AIM2 increases Tfh cell differentiation by activating the c-MAF signaling pathway, which in turn controls and sustains IL-21 production [32]. Another study revealed that the miR-21/BDH2 axis increases Fe²⁺-dependent TET enzyme activity and Bcl-6 gene demethylation in addition to driving iron buildup during Tfh cell differentiation [33]. B cells are crucial in SLE pathogenesis because they are the primary source of pathogenic autoantibodies. DNA methylation has been widely investigated in B cell activation and differentiation [34]. B lymphocyte-induced maturation protein 1 (Blimp-1) is essential for plasma cell development. A recent study has discovered that IL-10 increases the AIM2 expression by inducing DNA demethylation in B cells and that AIM2 directly binds to Blimp-1 and Bcl-6; thus, their expression levels are controlled [35].

2.2 Histone modifications

Histone modifications, another epigenetic mechanism, also contribute to SLE pathogenesis. Similar to DNA methylation, histone ubiquitination has a role in activating and suppressing gene transcription, which may be particularly crucial for time-sensitive processes, such as the execution of cell-cycle checkpoints, chromosomal segregation, and departure from mitosis [36]. Instead of relying on altered gene transcription, histone ubiquitination sends information to other proteins to trigger instantaneous reactions. A histone core is encircled by 146 base pairs or two turns of DNA to form a nucleosome. The specific amino acid residues of these histones, including lysine, arginine, and serine at specific positions, can be methylated, acetylated, ubiquitinated, phosphorylated, and SUMOylated [37]. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are responsible for acetylation and deacetylation, respectively. Moreover, EZH2, G9a, and other histone methyltransferases are the primary enzymes involved in histone methylation. Histone H3 lysine9 trimethylation and histone H3 lysine27 trimethylation (H3K27me3) result in gene silencing, whereas histone H3 lysine4 trimethylation (H3K4me3) activates gene transcription [38]. Global histone H3 and H4 hypoacetylations are discovered in lupus CD4⁺ T cells via H3K9 methylation [39]. Studies revealed that the H3K27me3 level is remarkably elevated in the HPK1 promoter in CD4⁺ T cells from SLE patients, with a notable reduction in Jumonji domain-containing protein 3 (JMJD3) binding [40–42]. Further study revealed that Th17 cell development is critically controlled by H3K27 demethylation, which is primarily mediated by the H3K27 demethylase JMJD3 [42]. Moreover, H3K27me3 is related to CD11a because its promoter locus has substantially lower H3K27me3 levels and higher JMJD3 binding in SLE CD4⁺ T cells than in healthy cells, thereby increasing T and B cell activities [41]. Our previous studies revealed that SLE CD4⁺ T cells have low levels of the transcription factor RFX1 [20,43,44], promoting IL-17A upregulation by increasing histone H3 acetylation and decreasing DNA methylation and H3K9 trimethylation in SLE CD4⁺ T cells [45]. Furthermore, RFX1 is strictly regulated by polyubiquitination-mediated proteasomal degradation through STIP1 homology and STUB1 [44]. Another transcription factor, E4BP4, recruits histone methyltransferase EZH2 and HDAC1 to the Bcl-6 gene promoter; it is also detected as impaired phosphorylation in SLE Tfh cells [46]. Moreover, the impaired E4BP4 is positively correlated with SLE disease activity [46]. The epigenetic component known as ubiquitin-like with plant homeodomain (PHD) and RING finger domains 1 (UHRF1), is downregulated; it is involved in increasing the Bcl-6 expression by lowering DNA methylation and H3K27me3 levels, thereby enhancing Tfh cell differentiation [47].

2.3 ncRNAs

Numerous autoimmune diseases in humans, including SLE, often exhibit aberrant ncRNA expression [48]. miRNAs are often the most extensively investigated ncRNAs in SLE. The investigations on the activities and roles played by miRNAs in developing CD4⁺ T cells presented fresh insights into the phenotypic and functional diversity of CD4⁺ T cells and the pathogenic process causing SLE [49]. Numerous studies demonstrated that miRNAs, such as miR-21, miR-26a, miR-29a, miR-31, miR-155, miR-101, miR-148a, and miR-183C, along with several newly identified long noncoding RNAs (lncRNAs), are remarkably altered in peripheral blood mononuclear cells (PBMCs) or CD4⁺ T cells from SLE patients; these miRNAs contribute to the onset of the disease by controlling abnormal activation and differentiation of CD4⁺ T cells [4,49–51]. In SLE patients, aberrant expressions of these ncRNAs have been associated with DNA hypomethylation, T cell overactivation, T and B cell tolerance loss, and autoantibody production [48]. Mature miRNAs, with a length of ~21 nucleotides, posttranscriptionally decrease gene expression by interacting with certain miRNA response elements on their target mRNAs [52]. Genetic variations rs767649 and rs13137 are linked to SLE susceptibility; in this regard, researchers have recently revealed that individuals with active lupus nephritis have substantially high levels of miR-21 and miR-155 in their PBMC, which may be used as biomarkers for SLE patients [53–55]. miR-21 may enhance the DNA demethylation of CD70 and LFA-1 mechanically by targeting DNMT1, which is essential for T cell hyperactivity [56]. Singh et al. demonstrated that the IL-12 levels in SLE patients are strongly connected with miR-21 expression, whereas the protein levels of IL-21 are favorably correlated with miR-25 and miR-186 expression [57]. In addition, Zhao et al. found miR-21-boosted intracellular iron buildup in lupus CD4⁺ T cells by decreasing the BDH2 expression; this occurrence contributes to global DNA hydroxymethylation and self-reactive T cells in SLE [43]. Additionally, the specific miR-21 expression inhibitor antagomir-21, which improves intracellular iron homeostasis and prevents Tfh cell proliferation in vivo, substantially inhibits the differentiation between Tfh cells and GC B cells [33]. Mice lacking miR-155 exhibits a diminished Th2 and Th17 response and considerably high expression of IFN-related genes (MX1, IP10, IRF7, and ISG15) [58]. Nevertheless, another study discovered that SLE patients have low levels of miR-142, miR-499a, and miR-155, which share murine double minute-2 (MDM2) as a target gene [59]. Despite miR-21 and miR-155, evidence shows that other miRNAs contribute to SLE-related abnormal CD4⁺ T cell differentiation. In SLE patients, the levels of miR-19b, miR-17, miR-20a, miR-21, miR-25, and miR-186 correlate positively with the SLE Disease Activity Index (SLEDAI) score, whereas miR-146a has a negative connection [57,60,61]. A recent study has revealed that the physical interactions between the miR-146a promoter and a cell-type-dependent miR-146a-specific distal enhancer cause NF-κB to bind to the disease-protective allele with sequence specificity, thereby increasing the expression of miR-146a in the PBMCs of SLE patients and inhibiting the activation of the type I IFN pathway [62]. miR-17-5p mimics decrease the transcript levels of the IFN-inducible gene MxA in SLE, thereby resulting in a remarkable decrease of E2F1 and c-Myc expression in SLE PBMCs [63]. In SLE patients and lupus mice, an increase in miR-590-3p expression is correlated with the upregulation of Th17 cell differentiation. Additionally, miR-590-3p causes apoptosis via blocking autophagy, thereby preventing Th17 cell proliferation; its enhanced expression can also alleviate the clinical symptoms of SLE [64]. miR-142-3p and miR-142-5p levels are substantially downregulated in CD4⁺ T cells in SLE patients compared with those in healthy individuals; they are also adversely connected with CD84, SAP, and IL-10, which are potential SLE-related targets [65]. Furthermore, researchers have recently found that Bcl-6 increases H3K27me3 levels and decreases H3K9/K14ac levels by recruiting EZH2 and HDAC5 in miR-142 promoter in SLE CD4⁺ T cells; this scenario leads to a decline in miR-142-3p/5p expression, which causes CD4⁺ T cell hyperactivity [66]. Nonetheless, further study is necessary to establish the precise mechanism of miRNAs in SLE.

X chromosome inactivation by X-inactive specific transcript (XIST) is a well-studied example of chromatin control by lncRNA because it ensures the correct X chromosome dosage [67]. lncRNA XIST was once regarded as mostly insignificant; nevertheless, mounting data indicate that its expression in female cells is a major factor in the sex bias found in SLE. The immune cells from SLE patients show the upregulation of X-linked genes and altered XIST localization; this finding indicates that defective X chromosome inactivation (XCI) maintenance may predispose women to autoimmune disorders [68]. Compared with healthy donors, SLE patients tend to have overexpressed genes typically silenced by XIST [69]. In the research, XIST-dependent genes, including Toll-like receptor 7 (TLR7), are typically overexpressed in the aberrant B cells of SLE patients because these genes lack DNA methylation in the promoter and need continuous XIST-dependent HDAC [69]. Despite XIST, other lncRNAs serve a crucial regulatory function in SLE. You et al. reported consistently increased AC007278.2 expression in SLE patients; in this scenario, the CCR7 transcription is inhibited by blocking its functional promoter, thereby modulating autoimmunity and follicular T-helper cell differentiation [70].

3 Bullous skin disease

Bullous skin diseases are characterized by bullae and blisters on the skin and mucous membranes [71]. In autoimmune bullous disorders, harmful autoantibodies can be found in the bloodstream and skin lesions. Pemphigus and pemphigoid diseases are the two clinically most prevalent kinds of bullous skin disease [72]. Pemphigus is a severe autoimmune disorder induced by autoantibodies that target desmosomal cadherins, such as desmogleins (Dsgs) and most likely desmocollins, which are necessary for initiating and sustaining intercellular adhesions between epidermal keratinocytes. Pemphigus vulgaris (PV), pemphigus foliaceus (PF), paraneoplastic pemphigus, and IgA pemphigus are the four primary members of the pemphigus group [73]. Pemphigus is caused by a confluence of genetic susceptibility elements, environmental variables, and aberrant immunological responses. Despite the identification of unique alleles for pemphigus, environmental susceptibility factors, including sunlight, high temperature, drugs, and herpesviruses, often cause changes in the epigenetic control of disease-relevant gene transcription [74] (Tab.2).

An increasing number of studies suggest that epigenetic dysregulation is associated with the onset and progress of autoimmune pemphigus. Zhao et al. discovered that the PBMCs from PV patients upregulate genomic DNA methylation, downregulate the levels of global histone H3, H4 acetylation, H3K4, H3K27 methylation, increase the levels of HDAC1, HDAC2, and SUV39H2, and decrease the levels of SUV39H1 and EZH2 [75]. Variations in the miRNA expression are identified in PV [76]. miR-424-5p is extensively expressed in the PBMCs of pemphigus patients, and its target genes are engaged in intracellular signaling cascades, phosphate metabolism, and kinase activity control [77]. Moreover, miR-338-3p is remarkably elevated in pemphigus individuals PBMCs with active lesions, and its expression is associated separately with disease severity and anti-Dsg3 antibody titers [78]. Mechanically, the upregulation of miR-338-3p may drastically inhibit RNF114 expression and contribute to Dsg3 antibody generation by suppressing TNFR-associated death domain (TRADD) expression and inducing the imbalance between the functions of Th1/Th2 cells [78,79]. In addition, the disease-associated single-nucleotide polymorphism (SNP) rs1805672 inside the 3′-untranslated regions (3′UTR) of killer cell lectin-like receptor subfamily-G1 (KLRG1) interacts directly with miR-584-5p binding, allowing for differential accumulation of KLRG1 mRNA, which may contribute to PF pathogenesis [80]. Pemphigoid diseases belong to a category of well-defined autoimmune disorders characterized by autoantibodies against dermal–epidermal junction structural proteins [72]. Pemphigus bullosa (PB) is the most common subepidermal autoimmune blistering disorder [81]. The levels of miR-1291 reveal a substantial positive connection with the baseline levels of serum CCL17 and anti-BP180, which are used as serum indicators for PB [82]. Epigenetics remarkably affects several molecular pathways involved in abnormal cell adhesion, which contributes to the development of bullous skin disease, thereby highlighting future research perspectives.

4 Psoriasis

Psoriasis is a common chronic autoimmune inflammatory skin disease that affects individuals in many internal, external, and psychological aspects [83]. The exact pathogenetic mechanism of psoriasis is particularly complex but not entirely elusive. A T cell-dominant immunological dysfunction is generally accepted to cause psoriasis; it also plays a remarkably role in the disease’s etiology, including the Th1/Th2 homeostasis, the IL-23/Th17 axis, and the Th17/Treg equilibrium [83]. Recent research has shown that epigenetic factors, such as dysregulated DNA methylation, aberrant histone modification, and miRNA expressions, contribute to the development and progression of psoriasis [84,85] (Tab.2).

4.1 DNA methylation

In our previous investigation, aberrant global DNA methylation exists in PBMCs and skin lesions from individuals with psoriasis vulgaris [86,87]. Aberrate CpG methylation in genes has been well studied with global methylation and specific gene in psoriasis patients [88,89]. CpG methylation is detected from the lesional epidermis; it is hypermethylated in genes such as p14ARF [90] and Sfrp4 [91], whereas p15 [92], p16 [90], p21 [92], and LINE-1 [93] are hypomethylated. Moreover, Zhou et al. discovered that numerous methylated genomic loci and the presence of psoriasis in skin and PBMC have a connection and several reactions, including the DNA methylation of the ECE1, MAN1C1, CYP2S1, DLGAP4, and EIFC2 genes [94,95]. Several new differentially methylated areas, including S100A9, PTPN22, SELENBP1, CARD14, and KAZN, are discovered by DNA methylation analysis in psoriatic skin and neighboring normal skin tissues. Methylation and gene expression are inversely correlated [96]. Compared with healthy skin, HLA-C methylation is considerably increased in nonlesional and lesional skin but not in HLA-A or B; it is also positively correlated with Psoriasis Area Severity Index (PASI) score [90]. In the psoriatic epidermis, cyclin-dependent kinase 2 (CDK2) activity is increased, but CDK4 activity is completely suppressed, according to recent research [97]. This phenomenon is due to a posttranslational control mediated by reduced expression of p27 and overexpression of p16 [97]. Mechanically, the promoter of the secreted SFRP4 in psoriatic skin has an abnormally high level of methylation. SFRP4 can inhibit the expression of the Wnt signaling pathway, which participates in regulating cell proliferation and differentiation [91]. Recent research has uncovered an epigenetic route in keratinocytes for skin inflammation modulation in psoriasis. This route is controlled by the interaction between transglutaminase 3 (TGM3) and TET3. TGM3 prevents promoter demethylation by inhibiting the recruitment of TET3 to the p65 gene promoter and phosphorylation of STAT3, leading to a decrease in proinflammatory cytokines and chemokines production [98].

4.2 Histone modifications

Histone modifications include acetylation, methylation, phosphorylation, and ubiquitination [99]. Global hypoacetylation of histone H4 is also identified in psoriatic PBMCs; this finding is inversely linked with disease activity as determined by the PASI score [100]. Another team found that the PBMCs from psoriasis patients have considerably lower levels of acetylated H3 and H4 alterations (changes frequently connected to transcriptional activity) and higher levels of H3K4 methylation than those of the control group [101]. Compared with healthy skin, psoriatic skin samples exhibit dysregulated HATs and HDACs. These enzymes maintain the overall equilibrium between histone acetylation and deacetylation [102–104]. Th17 and γδ T17 cells, characterized by the main cytokine IL-17A, are crucial for psoriasis pathogenesis [105,106]. H3K27 demethylation, largely mediated by the H3K27 demethylase Jmjd3, modulates Th17 cell development and cytokine production; this finding indicates the role of H3K27 demethylation in the pathophysiology of psoriasis and other inflammatory skin illnesses dominated by Th17 cells [42]. Furthermore, increasing the intracellular acetyl-CoA in psoriasis patients and mouse models exacerbates Th17 cell differentiation, which contributes to histone H3 acetylation of the Il-17a promoter; thus, this finding shows that intracellular acetyl-CoA plays a significant role in psoriasis pathogenesis [107]. Recent research has revealed that EZH2 and H3K27me3 are overexpressed in the epidermis of psoriatic lesional skin compared with those in the normal skin, demonstrating that EZH2 may be a therapeutic target for treating psoriasis [108]. Moreover, remarkable variations in methylation H3K27 are detected between biological drug (ustekinumab, secukinumab, adalimumab, and ixekizumab) responders and nonresponders, showing that the methylation of H3K27 and H3K4 may influence the responsiveness of psoriasis patients to biological treatments [101].

4.3 ncRNAs

Researchers found that ncRNAs are closely related to psoriasis pathogenesis. Considerable research showed that miRNA expression is much higher in psoriasis patients than in healthy individuals, suggesting that these molecules may have a role in the pathogenesis and act as an important target for psoriasis treatment [109,110]. Psoriasis is characterized by an imbalance of T lymphocyte subsets in the immune system, particularly Th17 cells. In addition, our research revealed that miR-210 level is highly elevated in T cells from both psoriasis patients and mice models, thereby stimulating Th1 and Th17 cell activation but restraining Th2 cells differentiation by lowering the expression level of STAT6 and LYN [111]. Additionally, imiquimod (IMQ)-induced psoriasis-like mice model administers nanocarrier miR-210 antisense, substantially downregulating the miR-210 in splenic CD4⁺ T cells and lesions, along with the ratio of Th1 and Th17 cells [112]. miR-340 may selectively bind to the 3′UTR of IL-17A and inhibit IL-17A production, thereby relieving a mouse model of psoriasis [113]. Small extracellular vesicles contain miR-381-3p-triggered polarization of Th1 and Th17 cells. In addition, miR-381-3p maintains RORt protein expression by binding the 3′UTR of the E3 ubiquitin ligase UBR5 [114]. miR-203, miR-21, miR-31, miR-146a/b, miR-184, miR-221, and miR-222 are increased under disease circumstances, whereas miR-99a, miR-424, miR-193b-3p, and miR-125b are downregulated. The most notable is miR-203, the first microRNA discovered to be remarkably overexpressed in psoriatic skin relative to healthy controls; it modulates cytokine signaling, hyperproliferation, and differentiation of keratinocytes [115,116]. The circulating miR-146a levels are elevated among psoriasis patients, particularly those with active disease [117]. Overexpression or inhibition of miR-146a reduces or promotes IL-17-driven inflammatory responses in keratinocytes, as shown by Srivastava et al. This finding indicates the importance of miR-146a in psoriasis pathogenesis and its therapeutic potential [118]. Furthermore, the upregulation of miR-146b is verified in psoriatic lesions, and miR-146b may modulate inflammation and keratinocyte proliferation in psoriatic skin by assisting miRNA-146a [119]. Additionally, increasing the SERPINB2 expression in the skin of psoriasis patients correlates positively with disease severity and negatively with miR-146a/b in psoriatic lesions; this finding suggests that SERPINB2 and miR-146a/b are components of a disease-related network of molecules that controls the inflammatory responses in psoriatic skin [120]. miR-31 is markedly overexpressed in psoriasis keratinocytes [121]. miR-31, directly induced by the NF-κB activation caused by inflammatory cytokines, also suppresses protein phosphatase 6 (ppp6c) expression and increases keratinocyte proliferation [122]. miR-21, which is markedly overexpressed in psoriatic skin lesions, inhibits apoptosis in activated T cells [123]. Furthermore, the overexpression of miR-21-3p in an IMQ-induced psoriasiform mouse model is linked with IL-22 production and function in vitro and in vivo and mediated through STAT3 and NF-κB signaling [124]. The high expression levels of miR-223, miR-143, miR-369-3p, miR-1266, miR-221-3p, and miR-31 in blood samples from psoriasis patients suggest that these microRNAs may serve as diagnostic biomarkers [125–130]. Although great progress has been made in locating the miRNA accountable for psoriasis, research on the diagnostic, therapeutic, and preventive uses of miRNAs is still required.

5 SSc

SSc, commonly known as scleroderma, is a complicated and highly heterogeneous autoimmune disease characterized by immunologic disturbances, vascular abnormalities, and accumulation deposition of extracellular matrix (ECM) proteins [131]. Early symptoms include skin tightness and itching; eventually, musculoskeletal injury, fibrosis, and vasculature are involved. The pathogenesis of this life-threatening illness is still not entirely understood [131]. Aberrant epigenetic changes have been related to SSc pathogenesis (Tab.2). Numerous cell types, including immune cells, fibroblasts (FBs), and microvascular endothelial cells, are linked to epigenetic alterations in SSc pathogenesis [132].

5.1 DNA methylation

CD4⁺ T cell abnormalities are one of the major causes of SSc pathogenesis. Our team first reported that a decreased DNA methylation level on the promoter regions of CD11a, CD70, and CD40L, as well as the low production of DNMTs, MBD3, and MBD4, is discovered in CD4⁺ T cells from SSc patients [133–135]. We previously reported that IFI44L is hypomethylated in SLE. These methylation variations can function as a blood biomarker for SLE. IFI44L expression is elevated in the whole blood of SSc [136]. A recent study has discovered differentially methylated regions associated with CD4⁺ T cell activation by using epigenomics and transcriptomics techniques; important SSc-associated susceptibility loci were also discovered [137]. Ding et al. discovered that both CD4⁺ and CD8⁺ in differentially methylated areas show a high hypomethylation enrichment of genes implicated in the type I IFN signaling pathway and considerably high amounts of IFN-related proteins in their serum [138]. DNA methylation alterations are also discovered in SSc endothelial cells. The bone morphogenetic protein receptor type 2 (BMPR2) gene, implicated in transforming growth factor β (TGFβ) signaling, is downregulated in SSc endothelial cells because of hypermethylation in the promoter region of the BMPR2 gene [139]. For SSc fibrosis, the predominant effector cells are FBs and myofibroblasts. SSc FBs exhibit large quantities of methyl cap binding protein-2, which targets methylated DNA and inhibits transcription [140]. Additionally, TGFβ causes an increase in the synthesis of DNA methyltransferases, thereby inducing the hypermethylation of the suppressor of cytokine signaling 3 promoter, an inhibitor of STAT3; this phenomenon ultimately results in the downregulation of the transcription factor [141].

5.2 Histone modifications

Posttranscriptional modifications of histones result in structural modifications of chromatin, which can permit or inhibit gene transcription [142]. A work published in 2019 discovered 1046 genomic sites with aberrant H3K4me3 and H3K27ac marks, which epigenetically imprint the activation of promoters and enhancers in SSc monocytes; these marks are related to aberrant gene expression [143]. Prior work indicated that monocytes are triggered by TLR8-modified histones to stimulate the release of profibrotic molecules from SSc patients [144]. Compared with endothelial cells from healthy people, the skin of individuals with SSc has high levels of HDAC5 and EZH2 [145,146]. SSc myofibroblasts include elevated amounts of HOX transcript antisense intergenic RNA, a scaffold long noncoding RNAs (lncRNA) known to drive the histone methyltransferase EZH2 to promote H3K27me3 in particular target genes, along with low levels of miRNA-34a [147].

5.3 ncRNAs

miRNAs inhibit gene expression by targeting the 3′UTRs of transcripts. Global miRNA-seq and mRNA-seq profiling of SSc monocytes demonstrated that the expression patterns of miRNA-485-3p and miRNA-26a-2-3p are verified and linked adversely with the pathogenic IFN signature [148]. Patients with SSc have more plasmacytoid dendritic cells (pDCs) in their blood than healthy persons, and miR-618 expression is enhanced in these pDCs [149]. The researchers established that miR-618 specifically binds IRF8, which controls the growth of pDCs. Moreover, miR-126 and miR-139-5p are highly increased in pDCs from SSc patients compared with healthy individuals [150]. Henderson et al. revealed that miR-27a-3p expression increases in dermal FBs from SSc patients in conjunction with decreased serum levels of Wnt antagonist sFRP [151]. In SSc lung FBs, miR-326 is markedly downregulated [152]. Similarly, in SSc FBs, the expression of miR-16-5p is suppressed, and inhibiting miR-16-5p boosts NOTCH2 expression and ECM deposition [153]. Furthermore, combined monitoring of blood miR-206 and miR-21 levels is more useful than detecting miR-206 or miR-21 alone for distinguishing scleroderma patients from healthy individuals; this finding suggests that clinical applications of microRNAs are conceivable [154].

RNA sequencing investigation revealed that the lncRNA negative regulator of interferon response (NRIR) is increased in SSc monocytes, with a high correlation with the IFN gene signature in SSc patients [155]. lncRNA H19X, which acts as an epigenetic regulator of ECM synthesis, is another lncRNA with significance to the SSc discovered in recent years [156]. Functionally, H19X controls miR-503 and miR-424 expression, which is considered to affect DNA damage-inducible transcript 4-like protein expression because of genomic conformation. This finding suggests that lncRNAs are potential therapeutic targets for SSc patients [156].

In these four autoimmune-related skin disorders, epigenetically aberrant genes are identified in peripheral blood and a substantial number of cells, including immune cells. Certain SLE-hypomethylated genes, such as CD11a, CD70, and CD40L, are also hypomethylated in SSc. Furthermore, type I IFN-related genes that play a crucial role in SLE are hypomethylated in SSc as well. Th17 and T17 cells, defined by the major cytokine IL-17A, exhibit abnormal epigenetic modifications essential for psoriasis pathogenesis. In SLE, the study of epigenetic modifications is somewhat widespread. The mechanism behind epigenetics is refined further. Recent research has indicated that epigenetic alterations, including DNA methylation, histone modification, and microRNAs in B cells and Tfh cells, play a key role in SLE pathophysiology. These epigenetic aberrations have the potential to function as biomarkers or therapeutic targets. However, a precise and complete understanding is needed to offer fresh insights into the connection between aberrant epigenetic changes and the mechanisms of the loss of tolerance of these autoimmune skin diseases. Furthermore, determining how these biomarkers can be transformed into clinical applications is crucial for the following phase.

6 Conclusions

Given the development of potent new techniques, studies on epigenetics published over the last few decades have identified multiple epigenetic aberrations in various autoimmune-related skin diseases. These epigenetic alterations have a remarkable impact on the four principal autoimmune-related skin disorders covered in this study, demonstrating a close relationship between epigenetic dysregulation and the pathogenesis of autoimmune-related skin disorders. Specific epigenetic dysregulations in autoimmune diseases may serve as possible disease biomarkers. One of our earlier studies demonstrated that the IFI44L promoter methylation level is a very sensitive and specific diagnostic biomarker for SLE. This research finding was successfully translated into clinical application. Instead of pyrosequencing IFI44L DNA methylation levels, our group has established a high-resolution melting technique that can be quickly accomplished using quantitative polymerase chain reaction [157]. Although various epigenetic regulations present insight into the possible biomarkers for diseases, the goal of using epigenetics to develop a stable diagnostic marker remains alluring. Despite clinical biomarkers, the development of precise epigenetic medicines as treatments for autoimmune skin disorders remains constrained. Striving to transform these epigenetic alterations into therapeutic therapies is worthwhile, notwithstanding the challenges in reaching the goal.

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