Epigenetics of autoimmune diseases

CHAPTER

Epigenetics of autoimmune diseases

8

Elham Farhadi, Mahdi Mahmoudi Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran

1 ­Introduction Autoimmune disorders are characterized by autoantibodies' production and the presence of autoreactive cells, which are the result of misdirection of self-antigens from foreign antigens. Autoimmunity has been associated with an imbalance between the presence of autoreactive cells and FOXP3+ suppressive cells [1]. Although genetic predisposition is one of the main factors in the etiopathology of autoimmune diseases (AIDs), autoimmunity is not just attained by genetic variations. Investigations on monozygotic (MZ) twins (who have the exact same genetic content) have shown that different phenotypes can arise from same genotypes and the penetrance of autoimmunity is about 20%–30%, thereby suggesting that epigenetics and environmental factors such as viral infection, nutrition, and exposure to chemicals can modify the genetic factors’ effects in the pathogenesis of autoimmune diseases [2, 3]. Discordance (which represents a function of prevalence) in MZ twins has been inversely related to disease prevalence. For example, the prevalence of rheumatoid arthritis with high discordance (80%) is about 1%, while the prevalence of osteoarthritis is around 20% with 40% discordance rate [4, 5]. Epigenetics is defined as the study of heritable changes in gene expression and activity without any changes in DNA sequences. Recent studies have shown involvement of epigenetic modifications in various autoimmune disorders. In autoimmune disorders, which are a multifactorial group of diseases, the interaction between genetics and environmental factors has been suggested to involve in predisposition and development of autoimmune diseases. Exposure to intrinsic (mutations, polymorphisms) and extrinsic (environmental agents) factors has been predisposed to autoimmunity [6, 7]. Alterations in epigenome in response to environmental factors, such as exposure to chemicals, can have effects on cellular function that may result in disease condition [8]. It has been supposed that, other than genetic predisposition, epigenetic mechanisms are involved in various disease phenotypes such as age of disease onset, disease severity, length of remission, and response to treatment. Epigenetic mechanisms, including DNA methylation, histone posttranslational modifications, and small microRNAs (miRNAs), have been shown to be involved in regulating several vital processes in the cells, namely, gene expression, DNA-protein interactions, cell differentiation (cells with the same DNA content differentiate to different cell types), embryogenesis, X-chromosome inactivation (resulting in more prevalent autoimmunity in women than men), and genomic imprinting [9–11]. Gene regulation acts as an important factor in cell-type development and differentiation, and provides a flexible state for the cell to adjust itself with environmental changes [12]. Prognostic Epigenetics. https://doi.org/10.1016/B978-0-12-814259-2.00009-1 © 2019 Elsevier Inc. All rights reserved.

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2 ­Epigenetic mechanisms 2.1  ­DNA methylation DNA methylation, which is one of the main epigenetic mechanisms, is a dynamic process that involves both methylation and demethylation events. Based on previous studies, DNA methylation has been documented to play a significant role in regulating gene expression during embryogenesis, cellular differentiation, and tissue-specific development [13]. DNA methyltransferase (DNMT) family, which includes DNMT1, DNMT2, DNMT3a, DNMT3b, and DNMT3L, are involved in DNA methylation. These enzymes transfer the methyl group from S-adenosylmethionine (SAM) as a donor to the 5′-carbon of cytosine. DNMT family is divided into two groups: de novo and maintenance [12]. DNMT3a, 3b act as de novo and DNMT3L is a cofactor for de novo DNMTs. De novo DNMTs are involved in DNA methylation during embryonic development. DNMT1 and DNMT2 are maintenance enzymes that act in DNA replication and on transfer RNA (tRNAs), respectively [14]. There are two types of DNA demethylation: active and passive. Active demethylation is performed through DNMTs downregulation and passive demethylation by activation-induced cytidine deaminase (AICDA) [15]. AICDA is involved in passive demethylation process by deamination of 5-methylcytosine (5-mC) to thymine (after methylation modification) [16]. Demethylation—the mechanisms that neutralize DNA methylation—can be active and passive. Passive demethylation is defined by inhibition of DNMTs function that is inhibited as a result of environmental factors such as therapeutic compounds to remove abnormal hypermethylation. Active demethylation is based on enzymatic function of cytosine deaminases, which mostly happens during cell differentiation and in immune cell activation process. Activation of this enzyme leads to deaminase of 5-methylcytosine [17]. While on one hand DNA methylation leads to suppression of transcription process, on the other demethylation of DNA sequences has been associated with progression of transcription. Methylation inhibits transcription through the methyl group interference with binding of transcription factors. It has been well established that most of the transcription factors bind to CpG sequences, so when the methyl group is added to these CpG sequences, transcription factors are not able to bind to DNA. Furthermore, there are some proteins, which have the methyl-CpG-binding domain (MBD), that bind to methylated DNA and repress transcription chromatin remodeling and heterochromatin formation [18].

2.2 ­Histone modifications Posttranslational histone modification has been shown to regulate expression of genes involved in essential biological processes, including DNA repair, DNA replication, and chromosome condensation [19, 20]. Histones, which are involved in packaging and organizing DNA, are highly conserved proteins. These proteins are categorized into two groups: core proteins (H2A, H2B, H3, and H4) and linker histones (H1 and H5). The posttranslational modification that occurs on amino acid residues of histones include acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and ADP-ribosylation [19]. Among these modifications, acetylation and methylation are well studied. Histone acetyltransferases (HATs) catalyze the addition of acetyl groups and histone deacetylases (HDACs) catalyze the removal of the acetyl groups [21, 22]. It has been shown that histone acetylation leads to euchromation configuration and activates gene expression, while deacetylation causes heterochromatin configuration, which interferes with transcription factors binding and suppress the transcription [23].

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In contrast to histone acetylation, histone methylation can result in both activation and repression of gene expression. The result of histone methylation depends on two factors: the number of methyl group that is added to amino acid residues and the type of amino acids, which are methylated. For example, trimethylation of histone H3 at lysine 4 (H3K4me3) leads to transcription activation due to reduced interaction between methylated histone and DNA, while dimethylation of histone H3 at lysine 9 (H3K9me2) is associated with suppression of gene expression [24]. Histone methyltransferases (HMTs) add the methyl group to lysine and arginine residues and histone demethylases (HDM) catalyze removing the methyl group(s) [25].

2.3 ­Noncoding RNA Noncoding RNAs belong to another group of epigenetic modifiers that regulate gene expression and have been categorized into several groups, including microRNAs (miRNAs) [26]. Among all these, miRNAs are well studied. miRNAs are short, single-strand RNAs (18–23 nucleotides) that bind to 3′-untranslated region (3′-UTR) of messenger RNA (mRNA) and regulate gene expression through various mechanisms. Complete binding of miRNA to 3′-UTR of target mRNA leads to degradation of mRNA by the RNA-induced silencing complex (RISC). Another mechanism is prevention of translation through reduction of ribosomal function [27].

3 ­The predominance of autoimmune diseases in females It has been estimated that autoimmune diseases affect 5%–10% of the population worldwide, of which females are 2.7 times more predisposed to autoimmune diseases [28]. Each autoimmune disease has been associated with a distinct female-to-male ratio. For instance, this ratio in diabetes mellitus type 1 is approximately 1:1, in multiple sclerosis (MS) is 2:1, in rheumatoid arthritis (RA) is 3:1, in systemic lupus erythematosus (SLE) is 9:1, and in autoimmune thyroiditis is 10:1 [29]. This increased predominance of autoimmune diseases in females has been linked with the presence of the extra X chromosome under normal conditions. In support of this hypothesis, some studies have shown that SLE predisposition in males with Klinefelter’s syndrome (47, XXY) that have an extra X chromosome is 14× more than (46, XY) males [30, 31].

4 ­Environmental factors contribute to increased autoimmune disease susceptibility through epigenetic modifications Given the fact that the exact etiology of AIDs is not clear, it seems that environmental factors may affect immunological tolerance and cause autoreactivity [32]. In the other words, exposure of individuals, who are genetically predisposed, to the environmental factors may lead to autoimmunity. It has been shown that environment results in DNA hypomethylation in T cells, which leads to expression of silenced genes. Furthermore, there are some evidence for environmental factors' role in impaired function of Tregs [33]. The most important cells in autoimmunity are Th1, Th17, and follicular T cells, while epigenetic mechanisms have been studied extensively in T and B cells in AIDs [34] (Fig. 1).

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FIG. 1 Internal factors such as genetics and oxidation and environmental factors like UV light, diet, drugs, chemicals, smoking, and infections are the strongest risk factors to develop autoimmunity through impact on immune system dysregulation.

4.1 ­Exposure to ultraviolet radiation Investigations probing the effects of sunlight and ultraviolet radiation (UVR) on the development of the AID have suggested both susceptible/protective roles in determining AID onset. It has been shown that exposure to UVR leads to induction of proinflammatory cytokines production like IL-1, IL-6, TNF-α, and vascular endothelial growth factor (VEGF) through NF-κB signaling activation [35]. On the contrary, UVR may have a protective role for disease onset through its role in production of vitamin D [36]. UVR is able to suppress immune responses by DNA hypermethylation, histone H3 phosphorylation, and hyperacetylation of histone H3 and H4 [37]. More UVR exposure and less use of sun protection in males may explain the lower prevalence of AIDs in males than females [38]. UV radiation of lupus peripheral blood mononuclear cells (PBMCs) leads to DNA hypomethylation which, is not dependent on DNMT1 level [39].

4.2 ­Diet Dietary components that provide methyl group have been shown to affect DNA and histone methylation. Micronutrients like folic acid [40], methionine [41], Zn, choline [42], and vitamins B2 [43], B6, and B12 [44] are methyl donors and have a positive correlation with SAM levels. Under conditions of oxidative stress, the expression of DNMT1 decreases. Therefore, higher level of SAM is essential for methylation reactions [45, 46]. Restriction of methyl-group donor such as methionine results in DNA hypomethylation. Hypomethylation of killer immunoglobulin-like receptor (KIR) and TNFSF7 in lupus patients as a result of restricted micronutrients leads to overexpression of these genes [47].

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In addition to this, obesity has been proposed as an important factor that can be used to determine autoimmune disease susceptibility [48]. For example, higher lipid content in MS patients with obesity has been associated with worse outcome [49]. High levels of leptin (lipid-derived hormone) lead to decreased number of Tregs in MS [50]. Researchers have found that reduced level of vitamin D is associated with increased MS progression. UVR exposure activates vitamin D to 1,25-hydroxyvitamin D3 in the skin [51]. In addition, it has been reported that 1,25-hydroxyvitamin D3 serum level is negatively associated with disease activity [52, 53]. It seems that vitamin D contributes to MS pathogenesis through effects on epigenetic mechanisms. Binding of 1,25-hydroxyvitamin D3 to its receptor results in HDAC2 recruitment to IL-17 promoter and repress IL-17 expression. Therefore, vitamin D deficiency exacerbates MS pathogenesis by alteration in histone modification and thereby inducing inflammation [54].

4.3 ­Drugs Various drugs have been reported to cause drug-induced lupus (DIL) by different mechanisms [55]. Among these, procainamide and hydralazine have been extensively studied [56]. Hydralazine induce DIL through epigenetic mechanisms, including antibody production against histone H3 and H2, indirect inhibition of DNMT1 through inhibition of extracellular signal-regulated kinase (ERK) pathway. Procainamide has been shown to act in different ways: direct inhibition of DNMT1 as a competitive inhibitor and by inducing antibody production against H2A/H2B complex [57]. Antihistone antibodies have been reported in SLE patients, which are associated with antidouble-stranded DNA (dsDNA) antibodies.

4.4 ­Chemicals Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly potent dioxin, leads to increased number of CD4+ CD25+ Treg cells through activation of aryl hydrocarbon receptor (AHR) [58]. Some researchers have shown that AHR regulates gene expression by modulation of epigenetic modifications [59, 60]. Trichloroethylene (TCE), an industrial solvent, was also reported to change DNA methylation [61]. Overall, exposure to different chemicals leads to increased synthesis of glutathione that conjugates with different chemicals. Increased glutathione is essential for protection against reactive species, which are produced due to metabolism of these chemical compounds [62]. Enhanced glutathione production causes lower level of homocysteine that results in decreased methionine and SAM. Therefore, overproduction of glutathione as a result of chemical exposure leads to DNA hypomethylation [63].

4.5 ­Smoking It has been revealed that smoking is involved in AIDs through epigenetic mechanisms like DNA methylation [64, 65], histone modification [66], and differential miRNAs expression [65]. Indeed, smoking has been identified as a risk factor for MS progression. So, in smokers, MS development is significantly higher than in nonsmokers [67]. Smoker patients with MS experience more relapses and there are more active brain lesions in MRI of these patients [68–70]. Hypermethylation of brain-derived neurotrophic factor (BDNF) has been reported in blood samples of individuals whose mothers smoked during pregnancy. BDNF contributes to differentiation and growth of neurons [71]. Global DNA hypomethylation

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as a result of smoking has been reported in rheumatoid arthritis [72]. Significant hypomethylation of F2R like thrombin 3 (F2RL3) promoter has been observed in RA smoker patients [64]. Similarly, the amount of F2RL3 methylation has been correlated to smoking-associated mortality in patients with coronary heart disease [73].

4.6 ­Infection Infection with Epstein-Barr virus (EBV) has been directly associated with MS disease onset through nuclear antigen of EBV [74]. Infection with EBV changes DNA methylation and miRNA expression pattern. For example, increased expression of miR-142-3p leads to enhanced immune tolerance, whereas overexpression of miR-155 correlated to central nervous system (CNS) inflammation [75, 76]. It has been reported that retroviruses may enhance autoimmune responses in two ways: encoding autoantigens and/or induction of genes that play a role in autoimmunity. HRES-1 and ERV-3 are the most common autoantigens that are encoded by endogenous retroviruses in lupus patients. Treatment with 5-azaC (DNA methylation inhibitor) leads to increased expression of these antigens. Thus, epigenetic mechanisms regulate the expression of autoantigens that are encoded by retroviruses [77] (Fig. 1).

5 ­Internal factors 5.1  ­Oxidation Increased level of reactive oxygen species (ROS) as a result of oxidative stress contributes in SSc pathogenesis [78]. It has been well documented that fibroblasts produce ROS in SSc in an ­inflammation-independent manner [79]. Oxidative stress involves in gene expression (dys)regulation through epigenetic mechanisms especially DNA methylation [80] (Fig. 1). The following subsections describe the major epigenetic mechanisms investigated in a few AIDs.

6 ­Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease, which is characterized by autoantibody production against nuclear, cytoplasmic, and surface antigens. These autoantibodies are produced by overactivated B cells [81]. The accumulation of immune complexes in different tissues and organs leads to inflammation and clinical symptoms like arthralgia or arthritis, skin lesions, and systemic disorders [82]. The etiopathology of SLE is not clear, but genetic factors, including major histocompatibility antigens (MHC), IL10, TNF, STAT4, PTPN22, BANK1, and ICAM3, have been shown to predispose patients to SLE [83–89]. Studies on identical twins who present incomplete disease concordance suggest that environmental factors and epigenetics are also involved in SLE pathogenesis.

6.1 ­DNA methylation As mentioned earlier, DNA methylation is one of the main epigenetic modifications that determine chromatin configuration and affect gene expression. In addition, DNA hypomethylation of various

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genes related to autoantibodies production in SLE, including antidouble-stranded DNA (dsDNA), antiSSA, anti-Sm, and antiribonucleoprotein antibodies, has been reported [90]. The X chromosome is demethylated in SLE women, which may explain the SLE predominance in females [91]. The content of hypomethylation is associated with SLE Disease Activity Index (SLEDAI) and the level of anti-dsDNA antibody [92]. The presence of apoptotic DNA is one of the SLE characteristics, which are related to lower ability of SLE patients in the clearing of apoptotic cells [93]. Injection of these apoptotic DNAs to BALB/c mice induces a lupus-like syndrome with anti-dsDNA antibodies production and lupus nephritis. The severity of this syndrome is associated with the content of hypomethylation of apoptotic DNA [94]. Defect in DNA methylation process leads to abnormal gene transcription that results in the development of different diseases. There are some evidence that show DNA methylation is involved in SLE progression. CD4+ T cells from SLE patients are hypomethylated [95]. It has been reported that DNMTs’ function is reduced in SLE patients, which is associated with DNA hypomethylation in this disease [96]. Demethylating drugs are the other evidence for DNA methylation role in SLE pathogenesis. 5-Azacytidine is a methylation inhibitor that leads to hypomethylation and autoreactive T-cell production, which responds to class II minor histocompatibility complex (MHC) antigens without any exogenous exposure [97]. The other methylation inhibitors like procainamide and hydralazine act through DNMTs inhibition directly or indirectly. Procainamide is direct inhibitor of DNMTs and hydralazine inhibits DNMTs by ERK pathway blockade [98, 99]. Injection of hypomethylated T cells, after treatment with these drugs, induces lupus-like disease in mouse. This issue confirmed that demethylation of DNA is sufficient for lupus development [100]. The effects of demethylating drugs are analyzed on different factors: T-cell antigen recognition, B-cell help, and interaction between T cells and macrophages. These drugs seem to affect T cells and make them autoreactive. DNA demethylation of T cells in lupus leads to upregulation of integrin adhesive receptors such as lymphocyte functionassociated antigen-1 (LFA-1) or CD11a/CD18, which has direct relationship with autoreactivity [101, 102]. LFA-1 is expressed on the cell surface of most cell types and contains two subunits: integrin alpha L (ITGAL) and the beta 2 chain (ITGB2). It has been reported that in autoreactive T cells in SLE patients, the promoter of ITGAL is hypomethylated, which leads to LFA-1 upregulation [103]. In autoreactive CD4+ cells in lupus patients, regulatory factor X1 (RFX1) is involved in autoreactivity and induction of CD11a and CD70 expression [104]. Upregulation of CD70 stimulates B cells in SLE patients [103]. Genome-wide methylation studies have reported some genes in different pathways like inflammatory cytokines (IL-4 [105], IL-6 [105], IL-10 [106], IL-13 [106]), and IL1R2 [107]), inflammation (CD40LG) [108], and cell lysis (perforin [109]) are demethylated in SLE and augment inflammation process. IFN type I-regulated genes are hypomethylated in SLE and result in lupus T cells' high response to IFN type I. It has been reported that this process is related to downregulation of DNMT1 as a result of defect in extracellular-signal-regulated kinases (ERK) pathway [110]. DNA hypomethylation is related to protein phosphatase 2A (PP2A), which phosphorylates MEK/ERK pathway [111]. Studies on transgenic mouse model have shown that defects in ERK pathway in female mouse (not male) lead to ERK-dependent predisposition to SLE [112]. It has been reported that decreased DNMT1 expression is associated with SLEDAI [96]. Demethylation of DNA occurs in B cells and PBMCs in SLE patients and associated with increased expression of some genes, including CD5, HTLV-1-related endogenous sequence 1 (HRES1),

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and ­lipocalin-2 (LCN2). CD5, under normal conditions, inhibits B-cell activation and hypomethylation of CD5 eradicates this inhibitory effect. HRES1 is correlated with autoantibody production [113]. In naïve B cells, the promoter of activation-induced cytidine deaminase (AICDA) is hypermethylated and this gene is suppressed, but naïve B-cell activation in ELS murine results in demethylation of AICDA promoter and production of IgG antinucleosomal antibodies [114]. Creation of 5-hydroxymethylcytosine (5-hmC) is another epigenetic mechanism in SLE patients and the level of 5-hmC in peripheral blood is correlated with SLE [115]. The oxidation reaction converts 5-mC to 5-hmC, and finally, 5-hmC promotes DNA demethylation [116, 117] (Table 1).

6.2 ­Histone modifications There are few data about histone modifications compared to DNA methylation in SLE. With regard to connection between DNA methylation and histone modifications, it is not surprising to see that alterations in histone modification are accompanied by changes in DNA methylation. For example, cAMP-responsive element modulator-α (CREM), which is a transcription factor, decreases IL-2 expression in SLE CD4+ T cells by histone deacetylation (by recruiting HDACs) and DNA methylation [150]. For the first time, use of histone deacetylase inhibitors showed that histone modification is involved in SLE pathogenesis. For example, trichostatin A (TSA) as a histone deacetylase inhibitor represses overexpression of IL-10 and CD40L (CD154) and induces the expression of IFN-γ, which is downregulated in SLE [151]. Mycophenolic acid enhances acetylation of H4 and trimethylation of H3K4 through histone acetyltransferase (HATs) and histone deacetylases' (HDACs) regulation on CD40L promoter, which leads to CD40L suppression [152]. Therefore, histone deacetylase inhibitors (like suberoylanilide and hydroxamic acids) not only confirm the histone modification role in SLE pathogenesis but also introduce new candidates for treatment of SLE and other autoimmune diseases [153]. Aberrant H3 and H4 acetylation was observed in T cells and monocytes that are involved in SLE pathogenesis. In SLE patients with active disease, the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been reported to be dysregulated [154]. In CD4+ T cells, while on one hand, H3 and H4 are hypoacetylated, on the other hand, H3 acetylation on lysine 18 leads to increased IL-10 in lupus [155, 156]. Acetylation of H4 in SLE monocytes is associated with increased expression of some genes such as IRF1, RFX1, and BLIMP1 (PRDM1) [155]. Furthermore, hyperacetylation of TNF-α promoter leads to TNF-α overexpression in SLE monocytes [157]. It has been reported that autoantibodies against acetylated histones, especially H2BK12, are associated with disease development [158]. Histone methylation enhances gene expression commonly, while demethylation represses transcription process [159]. It has been reported that HMTs like SUV39H2 and EZH2 are decreased in CD4+ T cells in SLE. Due to this issue, hypomethylation of H3 on lysine 9 in SLE CD4+ T cells occurs [160]. CD70, which is a costimulatory molecule for T cells, is upregulated in lupus patients. Acetylation of H3 and trimethylation of lysine 4 on H3 positively regulate CD70 expression and are associated with disease activity. H2A ubiquinated (UH2A) form is reported in renal biopsies of SLE patients who have nephritis [161]. In addition, autoantibodies against UH2A are detected in about 60% of SLE patients [162] (Table 2).

Table 1  DNA methylation in autoimmune diseases Epigenetic modification

Product/ function

Reference(s)

Hypomethylation Hypomethylation

Leads to LFA-1 upregulation Leads to downregulation of DNMT1

[103] [110]

Hypomethylation Hypomethylation

Leads to B-cell activation Leads to production of IgG antinucleosomal antibodies Leads to CD40L overexpression Leads to IL-6 overexpression Leads to CTLA-4 downregulation Leads to RASF activation Leads to chemotaxis and cell migration of RASFs Leads to antibody production and fibrosis Leads to increased B cell-T cell interaction Leads to T-cell proliferation, IgG production, and increased collagen expression Leads to Tregs abnormalities and disease activity Leads to increased collagen synthesis

[113] [114]

Cell type

Gene

SLE

T cells

ITGAL IFN type I-regulated genes CD5 AICDA CD40L IL-6 CTLA-4 LINE-1 CXCL-12, IL-10 CD40L CD70 LFA-1

Demethylation Hypomethylation Hypermethylation Hypomethylation Hypomethylation Hypomethylation Hypomethylation Hypomethylation

FOXP3 RUNX1 RUNX2 RUNX3 FLi-1 BMPs receptor II

Hypermethylation Hypermethylation

B cells

RA

T cells PBMCs Tregs RASFs

SSc

T cells CD4+ T cells Tregs

Endothelial cells Fibroblasts

MS

Lymphocytes CD4+ T cells White matter cells

DKK1, SFRP1 CTNNA2, CTNNB1, CTNNA3, CTNND2 SHP-1 FOXP3 PAD-2

Hypermethylation Hypermethylation Hypermethylation Hypomethylation Hypomethylation Demethylation Demethylation

Leads to MMP9 upregulation and suppression of some growth factors Leads to cell proliferation and survival Leads to activation of profibrotic pathway Leads to activation of Wnt/catenin pathway Leads to proinflammatory signaling suppression leads to Th1/Th2 and Treg/Th17 imbalance Leads to increased citrullinated-MBP, which may trigger autoimmune responses

[118] [119] [120] [121] [122, 123] [124] [125] [126] [127] [128, 129]

[130, 131] [132] [129] [129] [133] [134] [135, 136]

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Continued

6 ­ Systemic lupus erythematosus

Disease

212

Epigenetic modification

Product/ function

Reference(s)

Hypomethylation Hypermethylation Hypermethylation Hypermethylation

Leads to enhanced immune responses Leads to nephropathy Leads to global DNA hypomethylation –

[137] [138] [139] [140, 141]

Hypermethylation Hypermethylation Hypomethylation Hypermethylation

Leads to increased immune responses Leads to T-cell proliferation and activation

[142] [143]

Leads to reduced number of Tregs

[144]

LTA

Hypomethylation

Leads to follicular dendritic cell activation

[145]

GADD45

Hypomethylation

–

[143]

SHP-1 p16 p16 p15, p21

Hypomethylation Hypomethylation Hypermethylation Hypomethylation

Leads to proinflammatory signaling suppression Leads to increased proliferation Leads to lower hematopoietic proliferation Leads to lower hematopoietic proliferation

[146] [147, 148] [147, 148] [149]

Disease

Cell type

Gene

T1D

Monocytes PBMCs PBMCs PBMCs

GAD2, HLA-DQB1 UNC13B DNMT-1 E-cadherin, p16 (P16INK4a), CDH1, GDNF, MDR1 CD70 RUNX1 CD247 FOXP3

AS IBD

SjS

Psoriasis

CD4+ T cells T cells CD4+ FOXP3+ cells Salivary gland cells Salivary glands epithelial cells Fibroblasts Mononuclear cells of bone marrow

SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; MS, multiple sclerosis; SSc, systemic sclerosis; T1D, type 1 diabetes; SjS, Sjögren's syndrome; PBMC, peripheral blood mononuclear cell; RASFs, rheumatoid arthritis synovial fibroblasts; Tregs, T regulatory.

Chapter 8  Epigenetics of autoimmune diseases

Table 1  DNA methylation in autoimmune diseases—cont'd

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Table 2  Histone modifications in autoimmune diseases Disease

Cell type

Epigenetic modification

Gene alteration

Reference(s)

SLE

CD4+ T cells

Hypoacetylation of H3 and H4 Acetylation of H4 Hyperacetylation of TNF-α

Decreased IL-10 expression

[155, 156]

Increased expression of IRF1, RFX1, and BLIMP1 (PRDM1) Increased expression of TNF-α Increased expression of CD70

[155] [157]

Leads to SFRP1 downregulation ND Increased expression of TNF-α Decreased expression of HDAC2 and HDAC7 FLi-1 downregulation Increased expression of collagen Suppression of FRA-2 and decreased collagen synthesis Increased expression of COX-2 and TNF-α ND Increased expression of NF-κB E2F activation ND

[163, 164] [165] [166] [167]

Monocytes

T cells RA

RASFs

SSc

B cells Fibroblasts

T1D

Monocytes Beta-cells

Psoriasis

Keratinocytes PBMCs

Acetylation and methylation of H3 Increased EZH2 Increased SIRT1 Increased SIRT6 Hyperacetylation of H4 and hypomethylation H3 Hyperacetylation of H3 and H4 Decreased SIRT1 Methylation of H3 Hyperacetylation of COX-2 and TNF-α Increased SIRT1 SET7/9 methylate H3 SIRT1 downregulation Deacetylation of H4

[161]

[168] [169] [170] [171] [172] [173] [174, 175] [176, 177]

SLE, systemic lupus erythematosus; T1D, type 1 diabetes; SSc, systemic sclerosis; RA, rheumatoid arthritis; ND, not determined; PBMC, peripheral blood mononuclear cell; RASFs, rheumatoid arthritis synovial fibroblasts.

6.3 ­miRNAs Dysregulation of miRNAs, involved in three important mechanisms, has been reported in SLE patients: type I IFN pathway by direct targeting of key proteins that are involved in this pathway (IFN regulatory factor 5 [IRF5] and STAT1), DNA hypomethylation by direct or indirect inhibition of DNMTs, and inflammatory responses reinforcement by increased cytokine secretion. The expression of miRNAs is regulated by DNA methylation and histone modifications, and it has been observed that DNA hypomethylation and deacetylation lead to miRNA overexpression [178, 179]. Different studies on SLE PBMCs have shown that a range of miRNAs have been differentially expressed. It has been reported that three miRNAs (miR-21, miR-148a, and miR-126), which are overexpressed in lupus patients, are involved in DNA methylation. miR-21 and miR-148a cause hypomethylation by direct inhibition of DNMT1 [180]. It has been shown that miR-21 represses programmed cell death 4 (PDCD4) and PTEN that are involved in T-cell responses and B-cell activation, respectively [181, 182]. miR-126 by DNA hypomethylation results in induction of CD11a and CD70, which leads to T- and B-cell hyperactivation [183]. API5 is a molecule that contributes to apoptosis pathway andis regulated by miR-224. miR-224 is upregulated in SLE disease and is related to lupus pathogenesis [184].

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Some miRNAs in SLE T cells are downregulated, like miR-125a. Decreased miR-125a is involved in inflammation through CCL5 (RANTES) upregulation. miR-125a by negative regulation of transcription factor KLF13 regulates CCL5 expression. CCL5 is a chemokine that recruits the leukocytes to inflammation region, and CCL5 level in serum of SLE patients is significantly increased compared to healthy controls [185, 186]. Downregulation of miR-19b and miR-20a in SLE patients has been associated with increased tissue factor (TF) expression, which is involved in hypercoagulable state of lupus [187]. miR-145, which regulates STAT1 mRNA expression, is suppressed and STAT1 overexpression is associated with lupus nephritis [184]. Innate immunity is involved in SLE pathogenesis and Toll-like receptor 7 (TLR7) is one of the TLR molecules that plays an important role in innate immune system [188]. Based on a reporter study, miR-3148 was shown to bind to 3′-UTR of TLR7 mRNA and was shown to regulate its expression [189]. Single-nucleotide polymorphism (SNP) rs3853839 (C/G) has been reported in 3′-UTR of TLR7 mRNA that influences the binding of miR-3148 to TLR7 and gene expression. The presence of G allele which, is a risk allele, inhibits binding miRNA to mRNA and increased expression, while C allele leads to miRNA binding and mRNA degradation [189]. Early B-cell factor 1 (EBF1) is a direct target of miR-1246, which is reduced in SLE B cells; therefore, miR-1246 plays a role in lupus pathogenesis. EBF1 is involved in critical mechanisms through activation of AKT pathway such as development, B-cell activation, and proliferation. Therefore, downregulation of miR-1246 results in overexpression of EBF1 and B-cell hyperactivation [190]. miR-29b binds to 3′-UTR of DNMT3a and DNMT3b and regulates their expression and DNA methylation [191]. With regard to ETS1 gene regulation by miR-155, miR-155 has a main effect on anti-dsDNA antibody production [192] (Table 3).

7 ­Rheumatoid arthritis Rheumatoid arthritis (RA) is a chronic autoinflammatory disease that affects about 1% of the population. RA is characterized by massive inflammatory cytokine production by activated B and T cells as well as other cells such as RA synovial fibroblasts (RASF), which resulted in cartilage hyperplasia, cartilage, and bone destruction. The most prevalent clinical symptoms of RA, including swelling, pain, joint destruction, disability, and loss of function, have been reported in active state of disease. RA has two subsets based on the presence or the absence of antibodies against citrullinated peptide antigens (ACPA), which is the best predictor of disease outcome [221, 222].

7.1 ­DNA methylation Different studies have shown that DNA hypomethylation occurred in RASFs and PBMCs in RA patients compared to healthy subjects [223]. DNA hypomethylation in RA contributes to increased various gene expressions that are involved in different pathways like cell migration, cell adhesion, transendothelial migration, and extracellular matrix modulation [223]. It has been reported that decreased DNMT1 causes DNA hypomethylation in RASFs. It has been found that SAM and 5-mC are suppressed in RA, which is associated with enhanced expression of SAM decarboxylase (AMD), spermidine/spermine N1-acetyltransferase 1 (SSAT1), and polyaminemodulated factor-1-binding protein 1 (PMFBP1) [224]. Severe combined immunodeficiency (SCID)

Table 3  miRNAs changes in autoimmune diseases Cell type

Expression change

Epigenetic modification

SLE

PBMCs

Overexpression

miR-21, miR-148a, miR-126 miR-155

PBMCs

Downregulation

B cells CD4+ T cells

Downregulation Overexpression

miR-125a miR-145 miR-1246 miR-29b

RA

RASFs RASFs PBMCs and RASFs

Overexpression Downregulation Overexpression

miR-115, miR-203 miR-34a miR-155

SSc

Fibroblasts

Downregulation

miR-29a, miR-29b miR-145 miR-196a, miR129-5p, miR let-7a miR-150 miR-193b miR-30a-3p miR-129-5p

Overexpression

miR-21 miR-92a

Downregulation

miR-152

Microvascular endothelial cells

Gene alteration

Reference(s)

Inhibition of DNMT1, suppression of PDCD4, and PTEN Inhibition of DNMT1 Induction of CD11a and CD70 through hypomethylation Downregulation of ETS1/increased anti-dsDNA antibody production Suppression of KLF13/associated with inflammation STAT1 overexpression/associated with lupus nephritis Increased EBF1/B-cell activation and proliferation Suppression of DNMT3a and DNMT3b/ DNA hypomethylation Induction of MMP1 and IL-6 Increased XIAP expression and resistance to apoptosis Decreased MMP3 expression and inhibition of stimulatory effects of Toll-like receptor ligands and cytokines on MMP1 and MMP3 expression TGF-β signaling activation and collagen overexpression Overexpression of SMAD3/ increased fibrosis Increased collagen type I expression/tissue fibrosis Increased expression of collagen type I, SMAD3, and integrin beta3 Targets urokinase-type plasminogen activator (uPA)/ induces cell proliferation and inhibition of apoptosis Targets B cell-activating factor (BAFF) Targets collagen type I and connective tissue growth factor (CTGF) expression/increased fibrosis Downregulation of SMAD7 and COL1A1/increased fibrosis Downregulation of MMP1 Targets DNMT1/DNA methylation alteration

[180] [180] [183] [192] [185, 186] [184] [190] [191] [193, 194] [195] [193]

[196] [197] [198] [199] [200] [198, 201]

[202, 203] [204] [205]

215

Continued

7 ­ Rheumatoid arthritis

Disease

216

Expression change

Epigenetic modification

Overexpression

miR-34a, miR-155, miR-326 miR-326 miR-128, miR-27b, miR-340

Disease

Cell type

MS

Brain white matter cells CD4+ T cells

Overexpression

Tregs Oligodendrocyte

Overexpression Downregulation

T1D

Beta-cells Glomerular mesangial cells

Overexpression Overexpression

AS

PBMCs

Psoriasis

T cells Keratinocytes

Downregulation Overexpression Overexpression Overexpression Downregulation

CD4+ T cells

Overexpression

miR-223 miR-219 miR-338-5p miR-21 miR-192, miR216a, miR-217, miR-377 miR-130a miR-29 let-7i miR-203 miR-146a miR-125b

miR-210

Gene alteration

Reference(s)

CD47 downregulation/enhanced phagocytosis of myelin by activated macrophages/microglias Suppression of ETS-1/Th17 differentiation Decrease BMI1/Th2 to Th1 differentiation Decrease BMI1/Th2 to Th1 differentiation Decrease BMI1 and IL-4/Th2 to Th1 differentiation Decreased NF-κB/play a role in inflammatory responses Suppression of Sox6, Hes5, and Zfp238/oligodendrocyte differentiation inhibition Suppression of PDCD4/apoptosis resistance in beta-cells Modulation of TGF-β-regulated genes/enhanced expression of ECM proteins

[76]

Targets TNF-α and HDAC3 Downregulation of DKK1/bone-formation process Increased T-cell responses Decreased SOCS3 expression/active proliferation and abnormal differentiation of keratinocytes Decreased IRAK1 and TRAF6 expression/increased TNF-α expression Targets FGFR2/ induction of proliferation and aberrant differentiation Targets FOXP3/impaired Tregs function

[206] [207] [207] [207] [208, 209] [210] [211] [212–214]

[215] [216] [217] [218] [218] [219]

[220]

SSc, systemic sclerosis; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; MS, multiple sclerosis; T1D, type 1 diabetes; AS, ankylosing spondylitis; PBMCs, peripheral blood mononuclear cells; RASFs, rheumatoid arthritis synovial fibroblasts; Tregs, T regulatory.

Chapter 8  Epigenetics of autoimmune diseases

Table 3  miRNAs changes in autoimmune diseases—cont'd

7 ­ Rheumatoid arthritis

217

mouse models have shown that SSAT1 inhibition leads to matrix metalloproteinase 1 (MMP1) downregulation and defect in cell adhesion in RASFs [225]. CD40L, which is expressed on CD4+ T cells, is located on X chromosome. CD40L promoter is demethylated in RA T cells, which results in CD40L overexpression [118]. Nile et al. have reported that promoter of IL-6 is hypomethylated in RA PBMCs compared to controls, which leads to IL-6 overexpression in RA [119]. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is decreased in RA Tregs as a consequence of DNA methylation in CTLA-4 promoter. Hypermethylation of CTLA-4 resulted in impaired binding of nuclear factor of activated T cells 2 (NFAT2), which induces CTLA-4 expression [120]. Resistance to apoptosis is one of the main RASFs’ characteristics. Treatment with HDACs inhibitors like trichostatin A has revealed that epigenetic modifications are involved in apoptosis. For example, DNA methylation of death receptor 3 (DR3) in RASFs is correlated with resistance to apoptosis [226, 227]. Hypomethylation of long interspersed nuclear elements (LINE-1) prompter in RASFs leads to enhanced expression of LINE-1. LINE-1 upregulation results in p38 mitogen-activated protein kinases (MAPK), the c-Met receptor, and gelatin-3-binding protein, which are involved in RASF hypreractivation [121]. Hypomethylation of chemokine (C-X-C motif) ligand 12 (CXCL-12) and IL-10 promoters leads to CXCL-12 and IL-10 overexpression in RASFs, which contribute to chemotaxis and cell migration during disease [122, 123] (Table 1).

7.2 ­Histone modifications Zeste homolog 2 (EZH2), which is a histone methyl transferase, is increased in RASFs [163]. EZH2 contributes to transcription suppression through trimethylation of lysine 27 on histone H3 (H3K27me3) [164]. Furthermore, EZH2 regulates secreted frizzled-related protein 1 (SFRP1) expression, which is a Wnt signaling inhibitor in RASFs [163]. TNF-α that is overexpressed in RA causes upregulation of HDAC1 and HDAC nuclear function. So, it seems that alterations in HDACs in RA are an inflammation-dependent process [228]. In addition, it has been shown that TNF-α induces sirtuin 1 (SIRT1) expression that acts as a histone deacetylase in RA tissues. Increased SIRT1 is involved in critical events in RA, including induction of proinflammatory cytokine production in monocytes and RASFs, and resistance to apoptosis in RASFs [165]. HDAC inhibitors such as MI192, i.e., HDAC3-specific inhibitor, are able to block proinflammatory cytokine production like TNF-α and IL-1β in response to LPS stimulation in RASFs [229]. Different HDACs in various classes inhibit the stimulatory effect of TNF-α on IL-6 expression and the LPS effect on TNF-α and IL-6 gene expression in RA macrophages [230]. Altered histone sumoylation has occurred in RASFs. It has been reported that enhanced small ubiquitin-like modifier (SUMO)-1, accompanied by SENP1 downregulation, is observed in RA. Overexpression of SENP1, which is a specific protease for SUMO-1, leads to H4 acetylation suppression on MMP1 promoter and consequently MMP1 upregulation [231]. Some studies have shown that treatment with anti-TNF-α affects epigenetic mechanism, including increased ratio of HAT/HDAC in RA PBMCs [232]. SIRT6, which is associated with RA disease duration, is upregulated in RASFs of synovial tissues with high TNF-α level and in smoker patients [166].

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SIRT1, which is upregulated in RA synovial tissues, contributes to inflammatory processes and leads to resistance to apoptosis in RASFs [165]. Treatment with HDAC inhibitors results in apoptosis induction and proliferation inhibition by cell cycle arrest through acetylation of p21 and p16 promoters and overexpression of these proteins in RASFs [233]. Furthermore, HDAC inhibitors led to enhanced histone H4 acetylation, tissue inhibitors of matrix metalloproteinase 1 (TIMP1) upregulation, and increased the number of cells that express MMP3 and MMP13 [234]. It has been shown that an HDAC inhibitor named largazole (LAR) suppresses the expression of intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and MMP2 function through TNF-α pathway inhibition [235]. In addition, LAR is able to regulate HDAC1, HDAC5, and HDAC6 expression, and it has been confirmed that HDAC6 is involved in regulation of ICAM-1 and VCAM-1 expression [235] (Table 2).

7.3 ­miRNAs Recent studies have shown that miRNA expression changes in RA patients compared to healthy subjects. Studies on RASFs have shown that miR-115 and miR-203 are upregulated in RASFs compared to osteoarthritis’ fibroblasts. Increased expression of these miRNAs is associated with enhanced expression of MMP1 and IL-6. In addition, overexpression of these miRNAs has been correlated with DNA hypomethylation [193, 194]. Stanczyk et al. have reported that RASFs treatment by TNF-α leads to overexpression of miR-155 and miR-146. Studies on RASFs and PBMCs found higher levels of miR-155 in RA patients. In addition, miR-155 expression is upregulated upon treatment with IL-1, lipopolysaccharide, and bacterial lipoprotein. Increased expression of miR-155 results in decreased MMP3 expression and inhibition of stimulatory effects of Toll-like receptor ligands and cytokines on MMP1 and MMP3 expression [193]. miR-146, which is overexpressed in RASFs, is upregulated upon treatment with TNF-α and IL-1 [236]. It has been reported that miR-34a is downregulated in RASFs. miR-34a targets X-linked inhibitor of apoptosis protein (XIAP) directly, so decreased miR-34a is associated with high level of XIAP and resistance to apoptosis in RASFs [195] (Table 3).

8 ­Systemic sclerosis Systemic sclerosis (SSc) is a chronic autoinflammatory disease, which is characterized by microvascular damage, dysregulation of immune system (leads to autoantibody production), endothelial dysfunction, fibroblast activation, and excessive extracellular matrix deposition (ECM) resulting in skin and organ fibrosis [237]. With regard to severe tissue and organ involvement in SSc patients, the mortality rate of these patients is 3.24 times more than normal population [238]. SSc has two subsets based on the degree of skin involvement. When there is general fibrosis, SSc is classified as diffuse SSc (dcSSc), but when there is little skin fibrosis, SSc is classified as limited SSc (lcSSc) [239].

8.1 ­DNA methylation T cells have a distinct role in SSc pathogenesis. Generally, DNA hypomethylation, as a consequence of significant downregulation of DNMTs, MBD3, and MBD4, is observed in SSc T cells [240]. It

8 ­ Systemic sclerosis

219

has been found that histone H3 on lysine 9 was hypomethylated, which has direct association with SUV39H2 expression. Hypomethylation of CD40L prompter has been reported in SSc T cells, which leads to CD40L upregulation. CD40 (receptor for CD40L) is expressed on B cells and fibroblasts, so the overexpression of CD40L on T cells results in B-cell activation and antibody production and fibrosis process [124]. Lymphocyte function-associated antigen-1 (LFA-1 or CD11a), which is a costimulatory molecule on T lymphocytes, interacts with ICAM-1 on other cells. Promoter of LFA-1 gene is demethylated in SSc CD4+ T cells that result in increased LFA-1 expression. LFA-1 overexpression leads to CD4+ T-cell proliferation, increased IgG production, and redundant collagen synthesis by fibroblasts [126]. CD70, which is a costimulatory molecule for B cells, expressed on T cells, and a member of tumor necrosis factor family, is upregulated as a result of demethylation of its promoter and caused increased B cell-T cell interaction [125]. It has been reported that the number of regulatory T cells in SSc patients decreased compared to healthy control. Forkhead box protein 3 (FOXP3) gene, which is associated with disease activity and involved in Treg abnormalities, is suppressed due to its promoter hypermethylation. In addition, runt-related transcription factor 1 (Runx1) gene, which is a main transcription factor in Treg cells, is hypomethylated and downregulated [127]. RUNX family, including RUNX1 and RUNX2, upregulates collagen type II synthesis through enhanced expression of SOX5 and SOX6. RUNX3, which is induced by RUNX2, cooperates with RUNX2 to synthesize collagen [128]. The promoter of RUNX1, RUNX2, and RUNX3 genes is hypomethylated and the overexpression of these genes has been reported in SSc patients [129]. Friend leukemia integration 1 (Fli-1), which contributes to abnormal angiogenesis in SSc, is a member of ETS family. Fli-1 is expressed in endothelial cell, fibroblasts, and immune system cells and involved in proliferation, differentiation, and activation of these cells. Fli-1 is downregulated in SSc endothelial cells due to its promoter hypermethylation. Decreased Fli-1 results in MMP9 upregulation and suppression of some growth factors that contribute in SSc vasculopathy: platelet/endothelial cell adhesion molecule (PECAM)-1, platelet-derived growth factor (PDGF)-B, vascular endothelial (VE)-cadherin, sphingosine 1 phosphate (S1P1) receptors, CCN1, and CXCL5 [130, 131]. Bone morphogenic proteins (BMPs) receptor II, which is hypermethylated and decreased in microvascular endothelial cells, is involved in cell proliferation and survival. Downregulation of BMPRII leads to TGF-β and endothelin 1 (ET1) upregulation, which play a main role in SSc pathogenesis. Oxidative stress is able to trigger SSc and decreased BMPRII can cause sensitive cells to oxygen reactive species [132]. Enhanced expression of proteins that are involved in Wnt/β-catenin and suppression of endogenous inhibitors of Wnt leads to activation of Wnt signaling as a profibrotic pathway [241, 242]. Hypermethylation of regulatory sequences of Dickkopf-related protein 1 (DKK1) and SFRP1 that are endogenous inhibitors of Wnt pathway results in their downregulation. Promoter hypomethylation causes overexpression of key genes in Wnt signaling pathways such as CTNNA2, CTNNB1, CTNNA3, and CTNND2 in SSc fibroblasts [129]. Based on these data, epigenetic mechanisms lead to steady activation of Wnt/β-catenin pathway in SSc fibroblasts (Table 1).

8.2 ­Histone modifications B lymphocytes have a distinct role in SSc pathogenesis as they participate in autoantibody production; however, our knowledge about regulatory epigenetic mechanism in SSc B cells is low. However, generally, hyperacetylation of H4 and hypomethylation of lysine 9 on H3 (H3K9) have been reported to occur

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Chapter 8  Epigenetics of autoimmune diseases

in SSc B cells, which leads to decreased expression of HDAC2 and HDAC7 [167]. Hypomethylation of H3K9 is related to SUV39H2 downregulation in SSc B lymphocytes. These modifications are associated with disease activity and skin thickness and hardness [167]. Fli-1 expression is regulated not only by hypermethylation but also by histone deacetylation [168]. These epigenetic modifications lead to Fli-1 downregulation. Fli-1 binds to COL1A1 and COL1A2 genes (which encode collagen type I) and suppresses the collagen expression. Therefore, decreased expression of Fli-1 as a result of epigenetic alterations leads to excessive collagen synthesis in SSc disease. In addition, phosphorylation of Fli-1 on threonine 312 leads to addition of acetyl group to lysine 380 by p300/CREB-binding protein-associated factor (PCAF). This issue causes excessive fibrosis due to decreased interaction between Fli-1 and COL1A2 [130]. TGF-β, which is an underlying cytokine in SSc, leads to p300 (histone acetyltransferase) overexpression [243]. Sirt1, which is a histone deacetylase, is downregulated in SSc. Sirt1 activity results in increased expression of collagen and other genes that were induced by TGF-β/smad signaling pathway [169]. Epigenetic mechanisms can also play protective role. For example, trimethylation of lysine 27 on H3 is correlated with inhibition of fibroblasts function and decreased collagen synthesis due to suppression of fos-related antigen 2 (FRA-2) expression. Fra-2 is a member of AP-1 transcription factor family, which is involved in profibrotic signaling [170]. Given the role of histone modifications in SSc pathogenesis, many HDAC inhibitors are designed and used in clinical trials. For instance, trichostatin (TSA), which is used for myelodysplastic syndrome, can decrease collagen type I synthesis and modulate extracellular matrix turnover in SSc fibroblasts [168, 244] (Table 2).

8.3 ­miRNAs miRNA profiling of SSc patients has showed differential expression of various miRNAs. Upregulation of profibrotic miRNAs and/or downregulation of antifibrotic miRNAs contributes to fibrosis progression in SSc patients [245]. It has been reported that miR-29a and miR-29b are downregulated in SSc fibroblasts, which may be related to TGF-β signaling pathway. Decreased miR-29 family correlated to collagen overexpression and extracellular matrix deposition [196]. miR-21 has been upregulated in SSc skin fibroblasts compared to healthy subjects. miR-21 binds to 3′-UTR of SMAD7 and COL1A1 and represses their expression. SMAD7 is a negative regulator for fibrosis; therefore, increased miR-21 involves enhanced fibrosis by SMAD7 suppression [202, 203]. In addition, miR145, which downregulates SMAD3, has decreased in SSc skin fibroblasts. Therefore, miR-145 plays an antifibrotic role and contributes to TGF-β signaling which, is a fundamental pathway in fibrosis in SSc [197]. miR-92a has been significantly increased in SSc, which is induced by TGF-β signaling. MMP1, which involves in collagen deposition, is predictive target for miR-92a [204]. Diverse miRNAs have been reported to target collagen type I and suppress its expression in miR196a, miR-129-5p, and miR-let-7a. These antifibrotic miRNAs have been downregulated in SSc fibroblasts that lead to increased collagen type I expression, which contributes to tissue fibrosis [198]. There are few studies that evaluate miRNA expression in microvascular endothelial cells (MVECs) of SSc. These studies have reported miR-152 suppression in SSc-MVECs, which targets DNMT1. So, miR-152 contributes to SSc pathogenesis through DNA methylation alterations [205]. miR-150 has been decreased in SSc fibroblasts as a consequence of DNA methylation and its suppression

9 ­ Multiple sclerosis

221

has been associated with increased expression of collagen type I, SMAD3, and integrin beta3 [199]. Furthermore, it has been shown that miR-193b is downregulated in SSc biopsy samples. miR-193b targets urokinase-type plasminogen activator (uPA), which induces cell proliferation and inhibition of apoptosis in smooth muscle cells. Overexpression of uPA as a consequence of decreased miR-193b is a TGF-β-dependent process that is involved in SSc vasculopathy [200]. miR-30a-3p directly targets B-cell-activating factor (BAFF) in SSc fibroblasts and represses its expression. Elevated expression of BAFF in SSc fibroblasts has been related to miR-30a-3p downregulation. miR-30b-3p which has been downregulated in SSc, represses PDGF receptor B expression. It has been reported that the level of miR-30b is negatively correlated with Rodnan score and skin involvement [201]. miR-129-5p, downregulated in SSc fibroblasts, can regulate collagen type I and connective tissue growth factor (CTGF) expression. Therefore, miR-129-5p is an antifibrotic miRNA, where IL17A is able to enhance its expression and plays a therapeutic role in SSc [198] (Table 3).

9 ­Multiple sclerosis Multiple sclerosis (MS) is a chronic autoinflammatory and neurodegenerative disease of the central nervous system (CNS) [246]. MS is characterized by inflammation, demyelination, and remyelination processes. Inflammatory cells infiltrate from blood to brain that cause inflammation in the cortex and white matter [247, 248]. Initially, the CNS damage is reversible by remyelination process, but accumulation of damages ultimately leads to disability and loss of function [249].

9.1 ­DNA methylation There are some hypotheses that epigenetic mechanisms are involved in MS pathogenesis [250]. A whole DNA methylation study has shown that genes that are involved in immune responses are hypomethylated and genes that contribute to oligodendrocyte apoptosis are hypermethylated [251]. It has been reported that SHP-1 promoter, which is a tyrosine phosphatase and suppresses the proinflammatory signaling pathways, is hypomethylated, leading to SHP-1 overexpression. SHP-1 downregulation is associated with higher inflammatory function of lymphocytes [133]. Evaluation of CD4+ T cells in relapsing-remitting MS (RRMS) has shown that FOXP3 promoter is demethylated, which may lead to Th1/Th2 and Treg/Th17 imbalance. It seems that FOXP3 demethylation not only is able to inhibit Th1/Th2 differentiation but also induce Treg/Th17 differentiation [134]. In addition, some studies have found that the promoter of gene that codes IL-17A is hypomethylated. This hypomethylation plays a critical role in MS pathogenesis due to IL-17A effect on induction of Th17 differentiation [252]. It has been reported that myelin basic protein (MBP) changes play an important role in MS pathogenesis. Many researchers have found that increased citrullination of MBP occurs in MS patients, which leads to less stability of MBP and makes it an autoantigen that develops autoimmune responses [135, 253]. The enzyme that citrullinates MBP is peptidyl arginine deiminase type 2 (PAD2) that is hypomethylated in MS patients. This hypomethylation results in PAD2 overexpression and consequently increased citrullinated MBP, which may trigger autoimmune responses [135, 136]. Overexpression of DNMT1 and DNMT3a has been observed in MS patients, and is associated with apoptosis induction and neuronal cell death and degradation [254] (Table 1).

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9.2 ­Histone modifications It has been found that high level of histone acetylation is associated with inhibition of differentiation process in oligodendrocytes and enhanced expression of repressors of myelin expression [255, 256]. If demyelination occurs in the nervous system, deacetylation is important for myelin repair process [256]. Based on the recent studies, increased histone acetylation and increased level of repressors of myelin expression have been reported in MS patients compared to nonneurological controls [257]. In addition, it has been shown that the rate of acetylation is correlated with disease duration [257]. Another posttranslational histone modification is H3 citrullination, which is catalyzed by PAD4, but the real role of histone citrullination remains unclear [258]. It has been demonstrated that vitamin D deficiency contributes to MS pathogenesis through epigenetic modifications. Vitamin D uses histone acetyltransferase and/or histone deacetylase for regulation of its target gene expression [259]. Vitamin D acts through recruiting the histone deacetylase in CD4+ T cells and leads to deacetylation of IL-17a promoter. So, vitamin D deficiency has been associated with increased acetylation of IL-17a promoter and IL-17a upregulation, which is involved in Th17 differentiation [54] (Table 2).

9.3 ­miRNAs Overexpression of enzymes involved in miRNAs biogenesis such as Drosha, Dicer, and DiGeorge syndrome critical region 8 (DGCR8) in MS patients has been reported. Therefore, it seems that miRNAs play a critical role in MS pathogenesis [260]. Increased expression of miR-18b and miR-599 has been found in PBMCs of MS patients who are in relapse period [261]. Evaluation of white matter in MS patients' brain has shown that miR-34a, miR-155, and miR-326 have been upregulated compared to normal white matter. All these three miRNAs directly target CD47 mRNA and lead to decreased CD47 expression in the brain MS lesions. CD47 is an inhibitory molecule for macrophages/microglias; therefore, downregulation of CD47 results in enhanced phagocytosis of myelin by activated macrophages/ microglias and disease severity [76]. Upregulation of miR-155 has been observed in different cell types like macrophages, T cells, and B cells. Toll-like receptor ligands and proinflammatory cytokines are able to increase expression of miR-155; therefore, miR-155 plays a role in inflammatory responses [262]. Increased miR-326 has been associated with development of Th17 differentiation through suppression of transcription factor—ets-1. Furthermore, it has been reported that ets-1 is significantly downregulated in RRMS CD4+ T cells compared to healthy subjects [206]. Downregulation of miR-17 and miR-20a, which are able to inhibit T-cell activation, results in increased Th17 differentiation in MS patients [263]. Upregulation of miR-128, miR-27b, and miR-340 involved in the development of Th1 differentiation and the inhibition of Th2 differentiation has been observed in MS CD4+ T cells that are associated with disease severity [207]. These three miRNAs directly target B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and miR-340 targets IL-4; therefore, downregulation of these genes results in Th2 to Th1 differentiation [207]. In addition, miR-223 which regulates NF-κB signaling pathway and plays a role in inflammatory responses, has been overexpressed in MS Tregs [208, 209]. Overexpression of miR-155, miR-338, and miR-491 in the brain white matter in MS patients has been correlated with suppression of neurosteroids level in white matter through repression of aldo-keto reductase family 1 members C1 and C2 that contribute in neurosteroids biosynthesis [264].

10  Type 1 diabetes

223

Decreased miR-25 and miR-106b in MS contribute in Treg differentiation through regulation of TGF-β signaling pathway. CDKN1A/p21 and BCL2L11/Bim that mediate TGF-β signaling are direct targets of these two miRNAs [265]. Overexpression of miR-214 and miR-23a has been associated with the oligodendrocyte differentiation, while miR-219 and miR-338-5p inhibit the oligodendrocyte differentiation through suppression of Sox6, Hes5, and Zfp238 and affect remyelination. Inactive MS lesions indicate decreased miR-219 and miR-338-5p expression [210] (Table 3).

10 ­Type 1 diabetes 10.1  ­DNA methylation As previously stated, epigenetic mechanisms link the environmental factors to gene expression. It has been shown that high levels of glucose and free fatty acids are able to affect DNA methylation, thereby regulating the expression of genes involved in susceptibility to type 1 diabetes (T1D) and obesity [266]. A study by Padmos et  al. demonstrated that T1D monocytes exhibit abnormal gene expression profile [267]. Further investigations on T1D monocytes have shown that DNA methylation contributes to gene dysregulation. For example, the promoter of GAD2 and HLA-DQB1 is hypomethylated that leads to GAD2 and HLA-DQB1 overexpression. GAD2 encodes GAD65 that acts as an autoantigen and HLA-DQB1 presents extracellular antigens. So, upregulation of these two proteins results in enhanced immune responses [137]. Comparison between T1D patients and healthy subjects has been demonstrated that CpG islands, which are located before insulin promoter in T1D, are hypomethylated [268]. In early stage of diabetes, hypomethylated insulin DNA has been reported in blood samples, which may be associated with betacell death [269]. Investigations have been shown that UNC13B, which is associated with diabetic nephropathy (major complication of diabetes), is hypermethylated in T1D patients [138] (Table 1).

10.2 ­Histone modifications Recent investigations have shown that histone modifications play critical role in T1D pathogenesis, especially through recruiting HATs and HDACs that regulate key genes, which are involved in T1D pathophysiology [270]. Pdx-1 is a transcription factor that regulates insulin expression by epigenetic modifications [271]. In a high glucose condition, Pdx-1 induces insulin expression by recruiting p300 and CBP (histone acetyltransferases) and SET7/9 (histone methyltransferase) to change the chromatin structure at insulin promoter that leads to increased transcription of insulin [180, 271]. While in low glucose condition, Pdx-1 represses insulin transcription through HDAC1 and HDAC2, which deacetylates insulin promoter [271]. In addition, Pdx-1 is a specific transcription factor for regulation of SET7 expression [180]. These epigenetic modifications on the promoter of insulin have been reported only in the cells that produce and release insulin [272]. It has been shown that hyperglycemia in T1D monocytes leads to dimethylation of lysine 4 and lysine 9 on H3, thereby changing the expression of related genes [273].

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In diabetic nephropathy (DN), a major complication of T1D, TGF-β signaling plays an important role through upregulation of fibrotic and extracellular matrix genes like Collagen 1alpha 2 (Col1a2), plasminogen activator inhibitor 1 (PAI-1), and cell-cycle inhibitor p21 [274]. Transcription factors Smad2, Smad3, and Smad4 mediate TGF-β effects on gene regulation [274, 275]. Furthermore, it has been reported that activation of TGF-β pathway is involved in high glucose condition [274, 276]. So, inhibition of TGF-β pathway results in inhibition of epigenetic modification that was induced by high glucose such as SET7 recruitment [277]. High glucose levels lead to enhanced histone acetylation on the promoter of cyclooxygenase-2 (COX-2) and TNF genes, which cause overexpression of these genes in monocytes [171]. Under high glucose condition, oxidative stress leads to NF-κB pathway activation through p300 recruitment that results in upregulation of NF-κB-induced inflammatory genes [278, 279]. TGF-β induces PAI-1 and p21 expression by recruiting p300 and CBP to acetylate the sequences near the binding site of Smad and SP1, which bind to these two genes' promoters. Inhibition of TGF-βinduced gene expression by HDAC1 and HDAC5 overexpression confirmed the role of acetylation and HATs in TGF-β gene regulation [280]. SIRT1, which is a histone deacetylase, has been involved in T1D pathogenesis through contribution in various pathways like metabolism, adipogenesis, and insulin production [172]. SET7/9 methylate H3 lysine 4 on the promoter of NF-κB transcription factor in response to inflammation and leads to increased proinflammatory gene expression. The knockdown of SET7/9 has been associated with decreased proinflammatory gene expression, that was induced by TNF, due to decreased NF-κB p65 subunit [173] (Table 2).

10.3 ­miRNAs miRNAs are able to regulate the expression of genes involved in main pathways, which contribute to T1D pathogenesis like insulin production, metabolism, and adipogenesis [281]. Overexpression of miR-326 has been reported in lymphocytes of T1D patients with autoantibodies against glutamic acid decarboxylase (GAD) and insulinoma antigen 2 (IA-2) compared to T1D patients who are autoantibody negative [282]. Increased expression of miR-21 has been found in diabetic-mouse model that leads to programmed cell death 4 (PDCD4) downregulation. PDCD4 is a tumor suppressor factor that acts through Bax family proteins in apoptosis induction. So, downregulation of PDCD4 as a result of miR-21 upregulation leads to apoptosis resistance in beta-cells [211]. Investigation on T1D Treg cells has demonstrated that the expression of miR-342 and miR-191 is decreased while miR-510 is increased [283]. TGF-β treatment or high glucose condition has resulted in overexpression of miR-192, miR216a, miR-217, and miR-377 in glomerular mesangial cells. These miRNAs are involved in diabetic nephropathy through modulation of TGF-β-regulated genes. Increased expression of these miRNAs has been correlated to enhanced expression of ECM proteins like collagen and fibronectin [212–214]. High glucose level has been associated with miR-29a overexpression in adipocytes [284]. miR-320 makes the resistant adipocytes to respond to insulin [285], and miR-27b inhibits adipocytes differentiation [286]. miR-143, miR103, and miR-107 are able to induce adipogenesis. TNF-α treatment of adipocytes has been associated with downregulation of miR-143, miR-103, and miR-107. So, inflammation, cytokine secretion, and macrophage infiltration, as a result of TNF-α treatment, have been associated with adipogenesis suppression [287] (Table 3).

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11 ­Other autoimmune diseases 11.1  ­Ankylosing spondylitis Hypermethylation of SOCS-1 has been observed in HLA-B27-positive AS patients compared to HLAB27-negative patients. The content of methylation has been positively associated with inflammation degree, C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and serum level of IL-6 and TNF-α [288]. The promoter of DNMT1 is hypermethylated in ankylosing spondylitis (AS) PBMCs that result in DNMT1 downregulation and global DNA hypomethylation in AS [139] (Table 1). Evaluation of PBMCs of AS patients has demonstrated that miR-130a is downregulated in AS patients. miR-130a directly targets TNF-α and HDAC3 and suppresses their expression. Furthermore, HDAC3 recruitment to the promoter of miR-130a leads to decreased expression of miR-130a. With regard to increased expression of HDAC3 in AS patients, it seems that HDAC3 upregulation plays an important role in AS pathogenesis through miR-130a suppression and TNF-α overexpression [215]. Overexpression of miR-16, miR-221, and let-7i has been reported in AS T cells and increased miR-221 and let-7i have been associated with higher Bath Ankylosing Spondylitis Radiographic Index (BASRI) score. In addition, let-7i upregulation has been correlated to increased T-cell responses by IFN-γ production that involved AS pathogenesis [217]. miR-29 has been upregulated in PBMCs of AS patients, which directly targets DKK-1. DKK-1 is a negative regulator of Wnt pathway, which may involve in bone formation process in AS [216]. Suppression of PDCD4 by binding of miR-21 has been associated with activation of osteoclasts [289]. However, overexpression of miR-21 and PDCD4 has been reported in AS patients [290] (Table 3).

11.2 ­Inflammatory bowel disease Inflammatory bowel disease (IBD) is a chronic autoinflammatory disease that affects gastrointestinal tract in Crohn’s disease (CD) and colon in ulcerative colitis (UC). Although the exact etiology of IBD is unknown, it seems that aberrant immune responses to intestine microbiota, which lead to inflamed mucosa, are involved in IBD pathogenesis [291]. Epigenetic studies have shown that DNA methylation differentially changes in IBD patients compared to healthy subjects. Furthermore, DNA methylation of inflamed and normal tissues in IBD patients is significantly different [292, 293]. Genome-wide DNA methylation studies have reported that hypermethylation of some genes such as E-cadherin, p16 (P16INK4a), CDH1, GDNF, and MDR1 occurs in UC [140, 141] (Table 1). Evaluation of intestinal epithelial cells (IECs) has revealed that the expression of TLR2, TLR4, and its coreceptor MD2 is regulated by DNA methylation and histone modifications [294–296]. In addition, histone modifications and DNA hydroxymethylation are involved in regulation of the expression of antimicrobial peptide human beta-defensin 2 (hBD2) and CXCL16 in IECs, respectively [297]. miRNA profiling study has demonstrated that miR-192, miR-375, and miR-422b have been downregulated, while the expression of miR-16, miR-21, miR-23a, miR-24, miR-29a, miR-126, miR-195, and let-7f has been increased in UC patients [298]. In addition, miR-23b, miR-106, miR-191, miR-16, miR-21, miR-223, and miR-594 have been overexpressed in active CD tissue, while miR-19b and miR629 have been downregulated [299].

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11.3 ­Sjögren's syndrome Sjögren's syndrome (SjS) is a chronic autoinflammatory syndrome characterized by mouth and eye dryness as a result of lymphocytic infiltration to the exocrine glands [300]. Evaluation of bullous pemphigoid antigen 1 (BPAG1 or BP230) promoter has demonstrated that the prompter is hypermethylated, which has been associated with BP230 downregulation [301]. CD70, a costimulatory molecule in T cells, is encoded by TNFSF7 (tumor necrosis factor superfamily member 7) gene. The promoter of TNFSF7 has been hypomethylated in SjS CD4+ T cells compared to healthy subjects, which leads to increased CD70 expression. Overexpression of CD70 may involve in autoimmune responses in SjS patients [142]. Hypermethylation of RUNX1 (a transcription factor that contributes T cell development) and hypomethylation of CD247 (a gene that encodes ξ chain of CD3) has been found in SjS patients, which emphasize T-cell role in SjS [143]. In addition, hypermethylation of FOXP3 gene in CD4+ FoxP3+ cells leads to decreased expression of FOXP3 mRNA, which may contribute to reduced number of Treg (CD4+ FoxP3+) cells in Sjögren's syndrome [144]. A genome-wide DNA methylation study has revealed that the promoter of lymphotoxin-alpha (LTA or TNF-β) is hypomethylated. Increased expression of LTA has been reported in salivary gland tissue and serum sample of SjS patients. LTA is a subunit of a receptor on follicular dendritic cells (FDCs) that activates FDCs. Furthermore, knockdown of LTA in mouse model stops progression of SjS [145]. Evaluation of salivary glands epithelial cells (SGEC) has showed global DNA hypomethylation that has been associated with downregulation of DNMT1, growth arrest, and DNA-damage-inducible protein (GADD45 alpha) upregulation [143] (Table 1). With regard to overexpression of some miRNAs in SjS patients, it seems that miRNAs are involved in SjS pathogenesis. For example, miR-574-3p and 768-3p have been overexpressed in salivary glands tissue, and miR-150 and miR-146 show upregulation in both lymphocytes and salivary gland tissue [302].

11.4 ­Psoriasis Psoriasis is a chronic autoinflammatory disease that is characterized by skin lesions. Excessive keratinocyte proliferation and abnormal differentiation in keratinocytes lead to skin lesions. Dysregulation of immune responses through T cells, dendritic cells, and excessive secretion of proinflammatory cytokines contributes to pathogenesis of psoriasis [303]. Given the overexpression of DNMT1 in PBMCs of the patients with psoriasis, it seems that DNA methylation may be involved in psoriasis pathogenesis. So, upregulation of DNMT1 has been associated with global DNA hypermethylation in psoriatic PBMCs compared to healthy subjects [176]. SHP-1, which is a tyrosine kinase, has two promoters. Evaluation of CpG methylation in these two promoters has shown that the promoter 2 of SHP-1 is hypomethylated that results in increased SHP-1 expression in psoriatic skin lesions [146]. It has been reported that the promoter of p16 in psoriatic mononuclear cells of bone marrow is hypermethylated, which correlates to lower hematopoietic proliferation due to p16 downregulation, whereas the promoter of p16 has been hypomethylated in skin lesions of the patients with psoriasis [147, 148]. In addition, hypomethylation of p15 and p21 (cell-cycle regulators) has been found in psoriatic mononuclear cells of bone marrow that has been associated with lower proliferation of hematopoietic cells [149] (Table 1).

12 ­ Epigenetic biomarkers in autoimmune diseases

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Hypermethylation of p14ARF and ID4 (inhibitor of differentiation) has been reported in psoriatic PBMCs and skin lesions, respectively [176, 304]. Treatment of CD4+ T cells with anti-TNF in psoriasis patients has reversed the methylation level back to nonpsoriatic status [305]. Histone acetylation and deacetylation have been involved in psoriasis pathogenesis through upregulation of HDAC1, SUV39H1, EZH2 and suppression of HATs like p300, CBP, and SIRT1 [306]. Based on recent study, SIRT1 has been able to inhibit proliferation and induce normal differentiation of keratinocytes through E2F inhibition [174, 175]. So, downregulation of SIRT1 has been associated with higher proliferation activity of keratinocytes in psoriasis patients [174, 307]. Furthermore, deacetylation of histone H4 in psoriatic PBMCs has been found, which has been negatively associated with disease activity and Psoriasis Area and Severity Index (PASI) score [177, 307] (Table 2). Increased expression of miR-203 has contributed to active proliferation and abnormal differentiation of keratinocytes by SOCS3 (negative regulator of STAT3) and p63 repression. miR-146a overexpression has been involved in psoriasis pathogenesis through suppression of TNF-α regulators (IRAK1 and TRAF6) [218]. miR-125b downregulation has been reported in psoriasis that is related to induction of proliferation and aberrant differentiation due to increased expression of fibroblast growth factor receptor 2 (FGFR2) (direct target of miR-125b) [219]. miR-31, which directly targets serine/threonine kinase 40 (STK40), has been upregulated by TGF-β1 signaling in psoriasis. STK40 downregulation leads to NF-κB pathway activation, which results in enhanced inflammatory signaling [308]. Evaluation of CD4+ T cells in the patients with psoriasis has shown that miR-210 is significantly increased, which directly targets FOXP3. So, overexpression of miR-210 has been correlated in impaired immune responses due to FOXP3 role in Tregs [220] (Table 3).

12 ­Epigenetic biomarkers in autoimmune diseases Biomarkers that are indexes for biologic mechanisms are helpful for various issues, including diagnosis and classification, disease severity determination, prognosis prediction, and therapeutic effects monitoring [309]. New biomarkers, including epigenetic biomarkers, are effective for detailed classification and early diagnosis. Epigenetic biomarkers have been determined in some autoimmune diseases such as SLE and SSc. Hypomethylation of IL-1R2 and IL-10 in SLE patients is a potential biomarker that is positively associated with disease activity [107]. Increased level of IL-10 has contributed to autoantibody production and overexpression of IL-1R2 suppressed IL-1 signaling, and thereby, T-cell-mediated responses suppression [310]. In addition, hypomethylation of IL-6 promoter, which leads to IL-6 upregulation, is another biomarker for SLE. Hypomethylation of IL-6 has been associated with decreased level of complement in serum and enhanced production of autoantibodies and immune complexes (Table 4) [311]. FOXP3 gene, which is a key transcription factor for Treg differentiation, contains a conserve element named Treg-specific demethylated region (TSDR). In normal Tregs, TSDR has been completely demethylated. So, methylation of TSDR in Tregs is a biomarker for SLE and associated with disease activity. Furthermore, SLE treatment that results in quiescent stage of disease has caused decreased methylation level of TSDR in FOXP3 and increased number of Tregs [312]. The expression of CD11 has been positively associated with disease activity in SSc, while the expression of FOXP3 has a negative correlation with disease activity. Hypomethylation of CD11 and

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Table 4  Epigenetic biomarkers in autoimmune diseases Disease

Epigenetic biomarkers

Epigenetic biomarkers (miRNAs)

SLE

Hypomethylation of IL-2, IL-10, IL-6

miR-126, miR-21, miR-148a, miR-223-3p, miR-326 ↑

SSc

Hypermethylation of TSDR, trimethylation of H3K4 Hypomethylation of CD11 Hypermethylation of FOXP3 Hyperacetylation of histone H4

miR-142-3p ↑ miR-30b, miR-150 ↓

SSc, systemic sclerosis; SLE, systemic lupus erythematosus.

hypermethylation of FOXP3 promoters have been reported in SSc. So, the status of methylation of CD11 and FOXP3 promoters has been considered as a biomarker for SSc (Table 4) [126, 127]. Given the role of trimethylation of lysine 4 on histone H3 in SLE pathogenesis, researchers have reported that H3K4me3 can be considered as a biomarker [313]. Thus, H3K4 dimethylation and hypoacetylation, which increased in SLE, have led to positive regulation of gene transcription and associated with disease activity [152]. Hyperacetylation of histone H4 in SSc B cells, which is due to decreased HDAC2 expression, has been positively associated with disease severity [167]. Aberrant miRNAs expression has been involved in autoimmune diseases pathogenesis; therefore, miRNAs may be considered as biomarkers. For example, overexpression of miR-126 in SLE CD4+ T cells compared to normal T cells has been reported. miR-126 targets directly DNMT1 and causes DNA hypomethylation [183]. Large-sample size studies have revealed that miR-126 is a potential biomarker in SLE [314]. Increased expression of miR-21 and miR-148a in SLE T cells has been reported, which leads to decreased DNMT1 activity and DNA hypomethylation. In addition, miR-21 upregulation has been associated with disease activity [180, 181, 315]. Overexpression of miR-223-3p has a positive correlation with oral ulcer and lupus anticoagulant [316]. miR-326 upregulation has been positively associated with CRP, and C1q-antibody in lupus patients [317]. Downregulation of miR-30b, which has been negatively correlated with disease activity in SSc patients, leads to PDGFR-β suppression [201]. Overexpression of miR-142-3p, which has been associated with disease activity, is a biological marker for SSc [318]. Decreased expression of miR-150 (an antifibrotic miRNA) has been negatively correlated with disease activity in SSc [199] (Table 4).

13 ­Epigenetic therapy Investigations have shown that epigenetic mechanisms are involved in the pathogenesis of autoimmune diseases. New epigenetic biomarkers help researchers to use them for early diagnosis and design new therapeutic agents that have been named “epigenetic therapy.” Unlike genetic alterations, which are stable, it has been reported that epigenetic changes are reversible after drug treatment. Furthermore, conventional treatment with glucocorticoids has revealed that glucocorticoids induce antiinflammatory cytokine expression through histone acetylation [319]. So, some conventional drugs affect epigenetic modifications for disease treatment. Thus, DNMT inhibitors and HDAC inhibitors as well as oligonucleotides for miRNA silencing have been developed to affect epigenetic mechanisms and acted as new therapeutic agents.

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HDAC inhibitors, which have antiinflammatory role, are the most studied epigenetic drugs [230, 320]. Treatment with ITF2357, which is an HDAC inhibitor, has led to IL-17 downregulation and increased number of Treg cells by hyperacetylation of FOXP3. It has been believed that higher number of Tregs may contribute to decreased autoantibody production [321]. So, given the ITF2357 properties, it seems that it can be considered a potential therapeutic agent for SLE treatment. Some small molecules have been designed and developed for the bromodomain and extraterminal (BET) family such as BRD2, BRD3, BRD4, and BRDT. These small molecules are able to recognize lysine residues, which are acetylated [322]. With regard to BET family inhibitors' effects on induction of antiinflammatory cytokine production and suppression of Th17 function, these inhibitors can be a new therapeutic approach for AIDs treatment [323–325]. RASF treatment by I-BET151 has shown that I-BET151 is able to repress proinflammatory cytokines and MMP expression even in the presence of TLR ligands [325]. FK228, which is an HDAC1 and HDAC2 inhibitor, treatment has resulted in the induction of cell-cycle arrest by p21 upregulation, decreased TNF-α and IL-1β production, inhibition of synovial swelling as well as suppression of RASF proliferation (in vitro) [233]. Treatment of experimental autoimmune encephalomyelitis (EAE) mice with trichostatin A (TSA), which is an HDAC inhibitor, has resulted in neuronal survival improvement through suppression of proinflammatory signaling pathways [326]. Vorinostat is another HDAC inhibitor that decreases CNS inflammation and demyelination in EAE mice through inhibition of dendritic cells (DCs), effects on Th1 and Th17. In addition, Vorinostat treatment has been associated with decreased expression of CD80, CD86, and HLA-DR, which are costimulatory molecules on DC [327]. Valproic acid (VPA) that acts as an HDAC inhibitor has been able to suppress autoinflammatory responses by shifting differentiation of Th2 and Treg from Th1 and Th17 as well as downregulation of proinflammatory cytokines such as IFN-γ, TNF-α, IL-1β, and IL-17 [328]. Treatment with 5-aza-2′-deoxycytidine (decitabine) as a DNMT inhibitor in animal model of MS has been correlated to increased number and activity of FOXP3+ T cells and thereby reduced CNS inflammation and disease manifestations [329]. Given the successful effects of epigenetic therapy in some diseases, including cancer and autoimmune diseases, it seems that epigenetic therapy can be considered as a new approach for AIDs treatment.

14 ­Conclusion Based on genome-wide association studies, lots of genes have been identified that are involved in the pathogenesis of autoimmune diseases. However, only genetic factors cannot explain the pathophysiology of autoimmunity. Various studies have been shown that the interaction between epigenetic modifications, including DNA methylation, histone modification, and noncoding RNAs, affect gene expression and function. It has been well documented that epigenetic alterations are cell- and tissuespecific events. So, each cell type has a particular gene expression profile. Epigenetic alterations are reversible, which make them possible therapeutic targets. Epigenetic drugs, including DNMT inhibitors and HADCs inhibitors, have been studied on animal models and in clinical trial projects. In addition, miRNA targeting by mimics and inhibitors may be a new therapeutic strategy.

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Recent studies have identified the epigenetic mechanisms involved in the pathogenesis of autoimmune diseases. So, more studies can be done to determine the effect of epigenetic drugs on these mechanisms. DNMT1 inhibitor (decitabine) has been approved for the treatment of some malignancies. Histone deacetylase inhibitors have been defined as oncotherapeutic agents and are under investigation for autoimmune diseases.

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