Introduction

Epigenetics was defined by Conrad Waddington in the early 1940s as The branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being (1). Currently, epigenetics is defined as the study of changes in gene function that are heritable and that do not entail a change in DNA sequence (2). As has been mentioned before, all these mechanisms are heritable thus the epigenetic marks have the ability to persist during development and potentially be transmitted from offspring to offspring. These mechanisms play an essential role in: regulation of gene and microRNA (miRNA) expression, DNA-protein interactions, cellular differentiation, embryogenesis, X-chromosome inactivation, and genomic imprinting (3).

One of the main functions of epigenetics is gene regulation. Gene regulation plays an important role in determining individual gene function and activity, sets of genes which are functional in each specific cell type, cell type development and differentiation, and metabolic plasticity of the cell that allows it to adapt itself to environmental changes. But it is important to note that epigenetics is not the only determinant in gene function. There are intrinsic components that are stable over time and are the same in each cell type. These intrinsic components such as polymorphism and mutations are one of the mechanisms that affect gene expression. Also, the environment (virus, hormones, nutrition, and chemicals) influence epigenetics and the intrinsic components thus altering gene function (4).

The interaction between environment and epigenetics is only one of the mechanisms by which a large range of different phenotypes arise from the same genotype such as in the case of monozygotic twins. Monozigotic twins have an identical DNA sequence, but studies had found some phenotypical differences that may be the consequence of different exposure to environmental stressors. This exposure produces alterations in the DNA methylation pattern and histone modification (5,6). This approach may be one of the causes of the differences found in the concordance rate of autoimmune diseases between homozigotic twins (Table 1) (7–22).

Table 1

Concordance rate of autoimmune diseases between monozygotic twins.

Another example of how epigenetics interact with the environment is in the study of Agouti pregnant rodents. In this study, researchers fed Agouti pregnant rodents food rich in methyl donors and they found that the offspring of these rodents had a different coat color because of an altered DNA methylation process in comparison to the offspring of pregnant rodents fed a normal diet (Figure 1) (23). Other researchers showed that Dutch who were exposed prenatally to famine during Dutch Hunger Winter in World War II. Because of the lack of nutrients during the prenatal life of these individuals, there was a deficiency in methyl donors such as the amino acid methionine that causes the hypomethylation of the maternally imprinted insulin-like growth factor II (IGF-2) differentially methylated region (DMR) in comparison to unexposed and same sex siblings. The IGF-2 gene plays a key role in human growth and development, thus this finding supports the fact that early mammalian development is important for establishing and maintaining epigenetic marks (24,25).

Figure 1

Epigenetics – environment Interaction. Offsprings from Agouti pregnant rodent fed with food rich in methyl donors such as folic acid, had a different coat color because of an altered DNA methylation process.

Many studies had been done with the Dutch Hunger Winter cohort from World War II. One of them looked for differences in birth weight between offspring of mothers who were exposed to famine in early and late gestation. The authors found that epigenetic differences were found in individuals who were exposed to famine in early gestation but individuals also were born with a normal birth weight. In contrast, individuals exposed to famine in late gestation were born with low birth weight, but they didnt have any epigenetic changes (23). At the same time, other studies had demonstrated that those individuals exposed to famine during the gestational period have a higher risk of developing schizophrenia and dyslipidemia. One of these studies demonstrated that there are sex-specific differences in the pattern of atherogenic lipids at the age of 58. Women showed elevated serum concentration of total cholesterol, LDL, and tiglycerides in comparison with unexposed women (26,27). Also, it was found that exposed women had a wide range of indexes of body mass and thus had a higher risk of obesity and developing chronic diseases (28–30). Other studies have shown that individuals exposed to famine in early gestation have an increased risk of schizophrenia in both males and females, but individuals who were exposed in later gestation have a higher risk of developing affective disorder in the schizophrenic spectrum (31–33).

Nowadays, literature about how environmental factors may affect epigenetic mechanisms is increasing. Indeed in the last few years, some studies have investigated the relationship between socio-economic status (SES) and epigenetic differences, and their impact on risk and disease development. McGuinness D. et al., studied the global methylation content in individuals from the Glasgow-Based pSoBid cohort to elucidate differences in prevalence between more and less privileged groups. This work showed global DNA hypomethylation in the most deprived participants in comparison to more privileged ones, thus showing a relationship between hypomethylation status and biomarkers of cardiovascular disease and systemic inflammation such as an increase in IL-6 levels (34). Another study was done with forty adult males from the 1985 British Birth Cohort Study to look for the methylation state of promoters in individuals with extreme SES. Some limitations on the study are: individuals are only males and the blood samples were taken only in adulthood. However, authors found differential methylation in promoters for basic cell functions and signaling between SES groups (35). Tehranifar P.et al., used a cohort of US birth women to examine if early life and adult SES were associated with methylation of repetitive elements Sat2, Alu, and LINE-1. The results showed higher Sat2 and Alu methylation in individuals with low family income at birth which may predispose to disease development (36). As the study mentioned before, a limitation on the study was the use of a cohort of only women. Although all these studies give us a point of view of how SES affects the methylation status, it is important to mention that there is a lack of studies on gene-specific methylation status and SES. Also, it is important to remember that a variety of social conditions may affect methylation such as: diet, physical activity, alcohol intake, organic solvents, and pollutants in water and air (37,38). These studies are of great importance because it is known that cells may be influenced during development by environmental stressors that alter the epigenome and persist throughout life because it is maintained after mitosis. This could be an explanation for altered phenotypes and disease development (39).

Epigenetic mechanisms

There are different epigenetic mechanisms that regulate gene expression by activating or repressing gene expression: DNA methylation, histone modification, nucleosome positioning and RNAi (miRNAs and siRNAs) (2). It is important to mention that all these epigenetic mechanisms act together at the same time to regulate gene expression and not separately.

DNA methylation

DNA methylation occurs in different regions of the genome and it is important in the embryogenesis, cellular differentiation, and tissue-specific development. It is noteworthy that DNA methylation varies among tissues and cellular types because of a dynamic process involving methylation and demethylation events (40–42). Once there is an alteration in DNA methylation and demethylation patterns, it will give rise to dysfunctional cells and consequently disease. Methylation is mediated by the DNA methyltransferase (DNMT) family which is in charge of donating a methyl group to DNA 5-cystosine producing a 5-methylcytosine (5-mC). This family of enzymes has 5 members: DNMT1, DNMT2, DNMT3a, DNMT3b, and DNMT3L. At the same time, DNMTs can be classified into de Novo and maintenance DNMTs (Figure 2) (2). De Novo DNMTs are DNMT3a and DNMT3b, and they are in charge of methylation during embryonic development. DNMT1 is the maintenance DNMT, which is in charge of methylate hemi-methylated sites that are generated during DNA replication. DNMT2 acts on transfer RNA and DNMT3L acts on embryogenesis (43).

Figure 2

Classification of DNMTs. DNMTs can be classified in de novo and maintenance. de novo DNMTs are involved in methylation during embryonic development and maintenance DNMTs are involved in methylation during DNA replication.

The other mechanism that counteracts DNA methylation is demethylation. Demethylation can be passive or active (2). The first one is induced by inhibition of DNMT activities such as in the case of several drugs that are used as therapeutic compounds to erase aberrant hypermethylation. This inhibition produces the passive removal of methyl groups by the absence or dilution of the enzyme (44). Active demethylation, in turn, occurs in cell differentiation and has been found in the activation of immune cells (45). This process depends on cytosine deaminase in which its activation induces cytidine deaminase (AICDA) that deaminates 5-methylcytosine (46). Even though this was the first mechanism suggested, there is now evidence about three enzymatic families that activate demethylation: Ten-Eleven translocation family (TET), AID/APOBEC family, and the base excision repair glycosylases (BER). TET proteins (TET 1, 2, and 3) catalyze the conversion of 5-mC to 5-hidroxymethylcytosine (5-hmC). Furthermore this product is oxidized to 5-formylcytosine (5-fC) and 5-carboxylmethylcitosine (5-caC) (47). This conversion is followed by a deamination caused by the AID/APOBEC family of 5-hmC to 5-hidroxymethyluracyl (5-hmU). Here the active process of demethylation starts. The product 5-hmU is then replaced through the BER enzyme family to an unmethylated cytosine. The BER family is composed of a glycosylase member family such as thymine DNA glycosylase (TDG) and single-strand selective monofunctional uracil DNA glycosylase 1 (SMUG1). The function of these enzymes is DNA repair by the replacement of unstable products with unmethylated cytosines. They also interact with transcription factors, histone acetyltransferases, and de novo DNMTs (48–50). Moreover, there is evidence that RNA polymerase II interacts with 5-fC and 5-caC producing a signal for the recruitment of TDG and BER (51). All this information opens the door to new evidence about the demethylation mechanisms in gene imprinting. Hackett J. et al., demonstrated that demethylation in primordial germ cells occurs by TET1 and TET2 enzymes and this conversion to 5-hmC occurs in a temporal order depending on the imprinted Differentially Methylated Regions (DMR) (52).

It is important to understand that when there is a methylation state, transcription will be repressed; in contrast, when there is an unmethylated state, transcription will be permitted. Transcription inhibition is achieved because methyl groups interfere with the binding of transcription factors that activate transcription from a specific gene. Many of these transcription factors recognize mainly CpG sequences, but when these sequences are methylated they are unable to bind DNA. An additional mechanism of transcriptional repression involves proteins that are attracted to methylated CpG sequences. These proteins are part of a family methyl-CpG-binding domain (MBD), and they recognize methylated sequences to provide a further signal to alter chromatin structure by formation of a co-repressor complex (53).

There are four possible DNA methylation patterns. The first methylation pattern and the most widely studied is the methylation of CpG islands in promoter regions of genes. These CpG islands are regions of more than 200 bases with a G + C content of at least 50%. Many human gene promoters (60%) are associated with CpG islands and their basal state is unmethylated to allow transcription (Figure 3a) (53,54). The second pattern is DNA methylation of CpG island shores which are regions of lower CpG density in close proximity (~2 kb) to CpG islands. This pattern is similar to the CpG island methylation pattern in which methylation is closely associated with transcriptional inactivation. It is important to note that most of the tissue-specific DNA methylation occurs in these regions (Figure 3b) (53,55).

Figure 3

DNA methylation patterns. (a) Basal state of CpG islands is been unmethylated to allow the transcription, but when they are methylated at promoter regions of genes the transcription will be inhibited. (b) At the same time, CpG island shores located up (more...)

In contrast to both above mechanisms mentioned, the third pattern occurs in gene bodies where their basal state is to be methylated to avoid transcription, thus preventing spurious transcription initiations (Figure 3c) (56). In disease, gene bodies are demethylated to allow transcription initiation at incorrect sites. DNA methylation also take place at CHG and CHH (H = A, C or T) sites in the human genome. This methylation has been predominantly found in stem cells and seems to be enriched in gene bodies directly co-rrelated with gene expression. The last pattern is hypermethylation of repetitive sequences that protect chromosomal integrity by preventing reactivation of endoparasitic sequences, thus causing chromosomal instability, translocations, and gene disruption (Figure 3d) (57).

Histone modifications

Histones are conserved proteins that package and order DNA. These proteins can be grouped in core histones (H2A, H2B, H3 and H4) and linker histones (H1and H5). The linker histones bind to the DNA to seal off the nucleosome at the location where DNA enters and leaves (58).

Histones suffer some post-translational modifications such as lysine acetylation and methylation, phosphorylation, ubiquitination, SUMOylation, and ADPribosylation. Histone modifications play an important role in transcriptional regulation, DNA repair, DNA replication, and chromosome condensation (58,59). Of all these modifications, the one most widely studied is lysine acetylation. In this process histones are acetylated and deacetylated on lysine residues in the N-terminal tail. These reactions are catalyzed by histone acetyltransferases (HATs) or histone deacetylases (HDACs), respectively (60,61). HATs promote gene expression by transferring an acetyl group to lysine and HDACs promote gene repression by removing an acetyl group from the lysine tail (Figure 4). At present, it is known the presence of 4 classes of HDAC. Class I HDACs are localized in the cellular nucleus whereas class II shuttles between cytoplasm and nucleus. Class III HDACs are members of sirtuin family, and they are structurally different to the other ones because their activity depends on the cofactor NAD+. The last HDACs is the class IV which its only member, is HDAC-11 and it is found in the nucleus and has structural similarities with class I and II that are also metallohydrolyases dependent on Zn++ (Table 2) (62).

Figure 4

Histone Modification. To form heterochromatin, histone deacetylation of histone tails caused by HDACs enzymes in association with DNA methylation (M) confers a dense configuration of DNA that prevents its transcription. In the euchromatin state, there (more...)

Table 2

Histone Deacetylation Enzymes (HDAC).

Another group of enzymes playing a role in histone methylation are histone methyltransferases (HMTs) and histone demethylases (HDMTs). HMTs can add methyl groups to lysine residues at three sites to form a mono-, di-, or trime-thylated lysine. Also the methyl group can be donated to an arginine residue. It is important to mention that the site where the methyl group is added and the number of methylation may affect in a different way the chromatin structure and the gene expression. One of the most studied histone methylation is the methylation at lysine 9 on histone 3 (H3K9) (63). Activation of gene transcription is associated with H3K4, H3K36, and H3K79 whereas gene silencing and chromatin condensation is related to H3K9 and H3K27 (62,64,65). There are also two groups of demethylating enzymes which remove the mono- and dimethylations or all methyl groups from lysines. This family of enzymes is composed by the lysine-specific demethylase 1 (LSD1). LSD1 is a monoamine oxidase which uses a flavin adenine dinucleotide (FAD) as a cofactor to oxidize the amine group of methylated lysine (66–68).

It is important to note that histone modification may act together with DNA methylation states. An example of how these modifications act on transcriptional regulation is the histone deacetylation with the association of 5’ methylcytosine in the DNA which confers a heterochromatin configuration that makes DNA inaccessible to transcription factors. On the other hand, acetylation of histone tails (H3K9) and DNA demethylation causes euchromatin configuration which is accessible to transcription machinery (69). It is important to mention that many post-translational modifications can occur at the same histone tail and at same time to produce the repression or the activation of gene expression (70). For example, during the cell cycle, there is a regulatory relationship between methylation of histone H3 lysine 9 (H3K9) and phosphorylation of H3 serine 10 (H3S10). Phosphorylation of H3S10 is required for chromosomal condensation. During early prophase and anaphase, there are high quantities of H3S10 phosphorylation; in contrast, during late anaphase dephosphorylation occurs and H3K9 methylation reemerges. Therefore, H3S10 phosphorylation blocked methylation of H3K9 but not demethylation in the same residue permitting the access of transcription factors to DNA during mitosis. Also, phosporylation preserves methylation patterns during cell division (71).

miRNAs

miRNAs are 18 – 23 nucleotide RNAs in length that function as post-transcriptional regulators. They regulate mRNA translation by binding to complementary sequences that are cleavaged or repressed. Many miRNAs are transcribed from intergenic regions or from introns of protein-coding genes and, sometimes, they are expressed at the same time that is transcribed the protein gene. Just a few miRNAs have been located in exons of protein-coding genes. Of all these miRNAs, the intergenic miRNAs are the ones which have their own gene promoter and regulatory region (74).

The translational repression and target degradation of mRNAs is achieved by the level of complementarity between miRNA strands and the site in the 3’ UTR targets. If there is a complete complementation, there is a cleavage of the mRNAs and it will produce degradation. On the other hand, if there is an incomplete complementation, translation will be prevented by taking the transcripts into P bodies to keep them in a silenced state using proteins that prevent translation or removal of the cap structure. Another mechanism by which miRNAs affect gene expression is by histone modification and DNA methylation of promoter sites. This mechanism occurs thanks to RNA-induced transcriptional silencing (RITS) complex (Figure 5). This protein complex binds to miRNAs to do post-translational modification of histone tails such as methylation of lysine 9 of histone 3 to form heterochromatin and to cause transcriptional repression (74,75).

Figure 5

microRNA biogenesis. miRNA genes are transcribed by RNA Polymerase II in the nucleus forming a primary miRNA (pri-miRNA) with 100 to 1000 nucleotides in length. This pri-miRNA is recognized by nuclear enzymes Drosha, Pasha or DGCR8 (in humans) which cleave (more...)

Epigenetics and autoimmunity

Autoimmune diseases are a complex group of diseases with different epidemiology, pathology, and symptoms but with a common origin (76). All autoimmune diseases share immunogenetic mechanisms that are part of a pleiotropism of several repertoires of genes. Many studies over the years have shown that these diseases are caused by alterations at many loci and in genes of the human genome (77). But until recent years, epigenetic studies have been focusing on autoimmune diseases. Therefore, is important to underline that autoimmune diseases may be generated by many alterations in the same epigenetic mechanism. Also, it is essential to understand that epigenetics is not the only mechanism that may cause autoimmunity; instead there are intrinsic and extrinsic components (mutations, polymorphisms and environmental factors) that predispose to autoimmunity.

DNA methylation and autoimmune diseases

As we mentioned at the beginning of this review, DNA methylation is the most widely studied mechanism in autoimmune diseases. Several studies done so far have found that some diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have a global hypomethylation in promoter regions of DNA in their target cells (Table 3). The other autoimmune diseases are just beginning to be studied for methylation pattern.

Table 3

Summary of epigenetic mechanisms involved in autoimmune diseases.

Systemic lupus erythematosus

SLE is a systemic multiorgan autoimmune disease characterized by autoantibody response to nuclear and/or cytoplasmic antigens. Several studies have shown that there is a global hypomethylation of promoter regions that contain the genes that are overexpressed in the disease such as: ITGAL, CD40LG, PRF1, CD70, IFGNR2, MMP14, LCN2, and in ribosomal RNA gene promoter (18S and 28S) (78–82). The DNA hypomethylation may also affect the chromatin structure of T-cells thus enhancing the overexpression of these genes. This gene overexpression will cause cellular hyperactivity, perpetuation of the immune response and, consequently, perpetuation of inflammatory response (83–85).

An example of how hypomethylation alters gene expression in SLE is the hypomethylation of e1B promoter of CD5 in resting B cells. CD5 is a protein found in B cells that serves to mitigate activating signals from the BCR so that B cells are only activated by strong stimuli and not by normal tissue proteins. CD5 has two isoforms: e1A which is expressed on the membrane and e1B which is retained in the cytoplasm. The hypomethylation of e1B promoters may be the consequence of a reduced expression of DNMT1. Therefore, there is an increase in the expression of this CD5 isoform that will cause impairment in cell receptor signaling and thus promote autoimmunity (86). There are other studies where hypomethylation of the IL-10 and IL-1R2 genes is found in SLE patients and their relationship with disease severity. It is important to mention the importance of IL-10 for inhibition of T-cell function and encouragement of the B cell mediated function, while IL-1R2 interferes with IL-1 binding to its receptor IL-1R1 (87). Also, there is evidence of the abnormal expression of DNMT1 and MBD2 in PBMCs from SLE patients, in whom a decrease in the expression of DNMT1 and higher level of MBD2 mRNA was found in those patients. This finding is consistent with the state of global hypomethylation found in SLE patients (88). Moreover, in murine prone lupus models it is shown alteration within methylation pathway and S-adenosylmethionine (SAM) metabolisms, which is the enzyme in charge to donate the methyl group to cytosine. The product of SAM metabolism 5-deosy-5methylthioadenosine (MTA) may inhibit T cell activation, polarization to Th1 and Th2 and TCR-related signaling pathways and it was found decreased in these murine models. Thus, treating those mice with MTA enzyme ameliorated signs of lupus such as splenomegaly, lymphadenopathy, autoantibodies levels and IgG deposition (89).

Another example is in Lupus like disease caused by procainamide and hydralazine. These two drugs are DNA methylation inhibitors, thus they produce hypomethylation of DNA (90). In the case of procainamide, it is a competitive inhibitor of DNMT1 (91). Instead, hydralazine inhibits T and B cell signal-regulated kinase pathways (92). The kinase signaling pathway has in important role in the regulation of methylation (93). At the end, these two mechanisms produce a reduction in DNMTs that will enhance the gene expression of adhesion molecules on lupus drug-induced lymphocytes (94–96).

Rheumatoid arthritis

RA is a disease characterized by the progressive destruction of joints by invasive synovial fibroblasts. The RA synovial fibroblasts (RASFs) have a major role in the initiation and perpetuation of the disease (97). They are the reason of why several epigenetic studies of RA are focused in these synovial cells. Researchers have found a global hypomethylation of these cells which could be the responsible of overexpression of inflammatory cytokines in the synovial fluid (98–100).

Some examples of hypomethylation in RA are in CpG islands upstream of an L1 open-reading frame and IL-6 promoter gene in monocytes. L1 is one of the major classes of repetitive element that are interspersed in the genome. They are used as a marker because in normal synovial tissue they are methylated. In synovial tissue from patients with RA, L1 is hypomethylated as a consequence of reduce expression of DNMTs. This reduction of methylation in inflammatory response promoter genes causes an overexpression of growth factors and receptors, adhesion molecules and cytokines. At the end they will cause irreversible phenotypical changes that occur in synovial fibroblast (100,101).

The other example is the hypomethylation in CpG island within IL-6 promoter gene in monocytes. IL-6 is a pro-inflammatory cytokine that participates in B cell response. When this promoter is hypomethylated, there is an overexpression of IL-6 that will cause, at the same time, an overexpression of pro-inflammatory cytokines that will be associated with a local hyperactivation of the inflammation circuit (102). But there is evidence that in monocytes we can find also a mechanism of hypermethylation such as in the case of the CpG island within the promoter of death receptor 3 (DR-3). DR-3 is a protein that causes apoptosis and activation of transcription factor NF-kB, but when there is a downregulation of this protein because of the hypermethylation of its promoter, RA synovial cell will be resistant to apoptosis (103–105). Even though many of the studies have been done on PBMCs from RA patients, there are other studies that evaluate DNA methylation patterns from fibroblast like-synoviocytes (FLS). These studies have shown the association between differentially methylated loci with altered architecture and inflammation such as in the case of CHI3L1 (cartilage specific antigen), STAT3 (associated with IL-6 activation), TRAF2, TIMP2, ADAM12, CAPN8, TNFAIP8, CCR6, IL-6R, DPP4, and IL-1. All the genes found in this methyloma were involved in relevant pathways such as cell movement, adhesion, and trafficking (106,107). Another study shows that cytokine milieu may play an important role in epigenetic modification of FLS in RA. Authors showed that proinflammatory cytokines such as Interleukine 1 beta (IL-1β) and Tumor Necrosis Factor alpha (TNF-α) could suppress DNMT gene expression in FLS giving more evidence to global hypomethylation status of some key genes in RA pathogenesis (108).

Moreover, the enzyme MeCP2 in charge of gene silencing by DNA methylation and histone modification is found to be up-regulated in FLS isolated from RA murine models. Thus, this study found that MeCP2 may influence in the activation and maintenance of the Wnt pathway responsible of synovial hyperplasia, inflammation, pannus formation, and cartilage erosion during RA pathogenesis (109,110). Also, there is evidence of the influence of methylation states in other promoter regions that may be produced by exposure to some environmental hazards. It is known the influence of tobacco in the development of RA. An explanation of how this environmental toxin may influence in RA is because a DNA methylation change in the promoter region of GSTA2 gene which has a key role in detoxification of electrophilic compounds. In this same study was found some differentially methylated positions within MHC region that could influence in the genetic risk to develop RA (111).

Type 1 diabetes (T1D)

T1D is a T cell-mediated autoimmune disease that develops in genetically susceptible individuals affecting their endocrine pancreas. There are some mechanisms by which epigenetics may play an important role in T1D: by modulating lymphocyte maturation and cytokine gene expression and by differentiation of subtype T helper cells ruled by epigenetic controls. In this autoimmune disease in contrast to SLE and RA, there is a global hypermethylation activity caused by altered metabolism of homocysteine (112).

Glucose and insulin levels are determinants of methylation (113). They alter homocysteine metabolism by increasing cellular homocysteine production by its inhibition of trans-sulfuration (114,115). When there is an increase levels of homocysteine, methionine in cells will be catalyzed in DNA methyltransferases (DNMTs) by S-adenosylmethionine. This will enhance DNMTs activity that subsequently led to increased global DNA methylation. Also, an increase maternal homocysteine during pregnancy by a low protein diet can produce an alter methionine metabolism that will cause decrease islet mass and vascularity in the fetus with a subsequent glucose intolerance in adult life (116,117).

Moreover, studies in T1D have shown hypermethylation of FOXP3 promoter region in CD4+ T cells and higher levels of DNMT3b mRNA (118). In contrast, another study found hypomethylation of CpG-19, -135, and -234 proximal to TSS in the insulin promoter region that may be associated with the development of the disease (119). Epigenomic wide association studies (EWAS) have also shown methylated variable position in twins with T1D, suggesting that this difference may be one of the causes of different concordance rates (120).

Multiple sclerosis (MS)

MS is an inflammatory chronic disease characterized by myelin destruction followed by a progressive grade of neurodegeneration. Recent studies have shown that the promoter region of peptidyl arginine deiminase type II (PAD2) is hypomethylated (121). PAD2 has a key role in the citrullination process of myelin basic protein (MBP). This citrullination process has important biologic effects: promotes protein autocleavage increasing the probability to create new epitopes and, also, modulates the immune response. In MS we will find an increase demethylase enzyme activity which will cause hypomethylation of PAD2 promoter region (122). Because of this hypomethylation, it will be an overexpression of PAD2 that will increase MBP citullination process with subsequent increase production of immunodominant peptides. These peptides will increase the autocleavage of MBP causing irreversible changes in its biological properties producing proteolytic digestion, myelin instability, and a chronic inflammation response (123–125). Another protein with a role in MS pathogenesis is SHP-1, which functions as a negative regulator of cytokine signaling through STATs and NF-kB. In MS patients was found a hypermethylation of promoter 2 of this protein (126). Methylation also may influence in the state of the disease. A study found differences in DNA methylation pattern in Relapsing-Remiting Multiple Sclerosis (RRMS) between remission and relapsing patients (127).

Sjögren’s syndrome (SS)

There is little information about the role of methylation in SS disease. Even though, there is a study that shows BP230 hypermethylation and decrease in mRNA levels in labial salivary gland biopsies. This result shows that alteration in expression of genes coding for hemidesmosomes type I proteins (α6β4 integrins, BP180 and BP230) may cause basal lamina disorganization and modifications in localization and distribution of α6β4 integrins. As a consequence of these alterations, there will be an abnormal extracellular matrix – acinar cell communication, thus contributing to alterations in survival responses and cell death (128). Another study demonstrated the hypomethylation and upregulation in the expression of CD70 (TNFSF7) gene in CD4+ T cells from SS patients. It is important to mention the function of CD70 as a B cell co-stimulatory molecule that interacts with CD27 to initiate immunoglobulin production and cell differentiation (129).

Conclusions

Epigenetic research has grown to provide new insights into autoimmune diseases and this is possible thanks to advances in technological development which are enabling epigenomic analysis on a large scale. All this improvement in the genetic field has permit us to find new causes that may explain the etiology of autoimmune disease, showing us one more time that this group of diseases is not caused by a single altered component.

The candidate gene approaches have identified a small set of genes that undergo aberrant DNA demethylation and overexpression in systemic lupus erythematosus and rheumatoid arthritis which are the autoimmune diseases most widely studied in the last years. This identification of cell-specific targets of epigenetic deregulation in autoimmune rheumatic disorders will provide clinical markers for diagnosis, disease progression and response to therapies. But to achieve this, high-throughput approaches are necessary for screening epigenetic alterations in autoimmune disease related to specific tissue and cell types that are relevant to disease pathogenesis.

Once we have mapped all the altered epigenetic mechanisms that produce each one of the autoimmune diseases, we can research even more for therapeutic potential of compounds directed against those epigenetic mechanisms. But to do this, detailed human DNA methylomes, histone modification and nucleosome positioning maps in healthy and diseased tissues are needed.

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