Abstract SSc is an autoimmune idiopathic disease in which there is an inflammatory component driving fibrosis. The chief cell involved is the myofibroblast, which when activated secretes copious amounts of extracellular matrix that forms deposits, leading to stiffness and fibrosis. The fibrosis is most prevalent in the skin and lungs. In recent years epigenetic modifications have been uncovered that positively and negatively regulate the genesis of the myofibroblasts and that can be activated and regulated by a variety of cytokines and hormones. The epigenetic contribution to these cells and to SSc is only now really coming to light, and this opens up a new therapeutic target for the disease for which many epigenetic drugs, such as miRNA replacements, are beginning to be developed. This review will examine the epigenetic regulators in the disease and possible targeting of these. fibrosis, epigenetics, methylation, histones Rheumatology key messages Epigenetics is critical in SSc. Activation of myofibroblasts is associated with multiple epigenetic changes in SSc. DNA methylation inhibitors may be useful in SSc. Introduction SSc is an autoimmune connective tissue disease with no known cause. The disorder is characterized by vascular disease, inflammation and fibrosis. Although overall survival of the disease has increased, no specific therapy that modifies the fibrosis exists . The activation of fibroblasts to myofibroblasts is a key event in the disease. The latter cell type secretes high amounts of extracellular matrix (ECM), producing a smooth-muscle-like phenotype. Epigenetics refers to alterations of gene expression without a change in the DNA sequence. There are three principle mechanisms through which epigenetics operates: miRNAs, DNA methylation and histone tail modification. These modifications alter the gene expression through various mechanisms that, importantly, are rapid and reversible. They are modified by the local microenvironment in response to various cues. The fibrosis is due to an aberrant wound healing response through the dynamic modifications of the ECM  and it is reasoned that this could be underpinned by epigenetic changes. Epigenetic changes can alter the phenotype of the cell profoundly, and recent data have revealed a role for epigenetic modification in SSc. This review will briefly examine the role of epigenetics in SSc with a particular emphasis on the myofibroblast. Histone modifications in SSc The nucleosome is a major part of chromatin and is composed of four different histones that form an octamer (H3, H4, H2A and H2B) . This structure allows large amounts of DNA to be packaged into a relatively small nucleus. The nucleosome is highly modifiable, which allows the DNA to be accessible or inaccessible for transcription . Post-translational modifications of the chromatin determine accessibility. The histones are globular in nature except for their tails. It is in the histone tails that there can be multiple modifications of which at least eight are now known. These histone tail modifications include methylation, acetylation, phosphorylation , ubiquitination, citrullination, sumoylation and adenosine diphosphate ribosylation . Furthermore, there are families of enzymes that mediate these histone modifications, such at the histone acetyltransferases (HATs) that catalyse the addition of an acetyl group from a donor, acetyl-CoA. Hyperacetylation of histone tails results in opening up of the DNA and thus permits access to transcription factors promoting gene expression. There are also enzymes that remove the modifications from the histone tails, such as the histone deactylases (HDACs), which remove the acetyl groups leading to a closed chromatin structure and therefore gene repression . Acetylation is by far the most common histone modification. A few papers have demonstrated HDAC alteration in SSc . HDAC7, a class IIb HDAC, has been found to be dysregulated in SSc. Small interfering RNA (siRNA)-mediated silencing of HDAC7 resulted in much reduced collagen expression in SSc dermal fibroblasts, and the broad spectrum HDAC inhibitor trichostatin A (TSA) reduced HDAC7 expression. Wang et al.  also found that incubation with TSA reduced collagen deposition through hyperacetylation. A similar effect of broad spectrum inhibition was found in a cardiac fibrosis model . While the HDACs remove the acetyl groups from the histone tails, the HATs add the acetyl groups onto the histones, and the balance between the HATs and the HDACs is of key importance for the overall acetylation . The enzymes that add the acetyl groups are sometimes referred to as the writers and the removing enzymes as the erasers. P300 is one of the main HATs that has been found to be up-regulated in SSc fibroblasts , and forced overexpression of P300 in normal dermal fibroblasts enhanced TGF-β1-mediated collagen increases . Furthermore, in an animal model of SSc, elevated levels of P300 have been demonstrated in the skin . In the bleomycin model of skin fibrosis, it was demonstrated that treatment of the animals with TSA reduced fibrosis through blocking HDAC3, leading to re-expression of Wnt inhibitory factor 11 and reduction of Wnt-mediated signalling . Wnt inhibitory factor 11 is critical in regulating the Wnt signalling pathway  and blocking unrestrained collagen expression through β-catenin . Sirtuin-1 (Sirt1) is a non-classical HDAC that is dependent on NAD+ as a cofactor. It is most famous for being associated with increased lifespan. It has been found to be down-regulated in SSc skin and SSc fibroblasts . One study found that induction of Sirt1 with the phenolic compound resveratrol reduced collagen and other ECM molecules . However, another study found Sirt1 fibroblast-specific knockout (KO) mice had reduced fibrosis . The reason for this disparity may be the use of a chemical vs a fibroblast-specific KO model. Sirt1 has also been found to negatively regulate MMP levels in dermal fibroblasts . The histone H3K9 demethylase enzyme Jumonji domain containing 1A (JMJD1A) is a protein that catalyses the removal of methyls from H3K9 mono- and dimethylated histones; it is critical in sex determination  and contains a Jumonji C domain. JMJD2B levels are associated with epithelial to mesenchymal transition, and reduction of JMJD2B results in reduced markers of the transition . Furthermore, PHD finger protein 8 (PHF8) histone demethylase regulates mesenchymal formation  and it could be the case in SSc that these enzymes are elevated leading to enhanced fibrosis. JMJD3 is the enzyme that demethylates histone H3 lysine 27 , and it was recently shown to be up-regulated in SSc dermal fibroblasts . It was found that pharmacological inhibition of JMJD3 with a small molecule inhibitor reduced fibrosis in multiple animal models . This was found to be due to the accumulation of the H3K27Me3 mark at the promoter of Fra2 that thereby repressed Fra2 expression . In a similar fashion, in SSc fibroblasts inhibition of H3K27 histone trimethylation by inhibition of the enzyme enhancer of zeste homologue 2 (Ezh2), a SET-domain-containing methyltransferase, with 3-deazaneplanocin A (DZNep) results in increased ECM production. The underlying mechanism is reduced H3K27 trimethylation leading to up-regulation of the activator protein 1 (AP-1) family member transcription factor Fos-related antigen 2 (FRA-2), and this leads to the fibrosis . Thus in SSc it appears that Ezh2 is antifibrotic  as inhibiting this chemically promotes fibrosis, although in liver fibrosis it appears pro-fibrotic as in vivo inhibition results in reduced liver fibrosis using DZNep-loaded liopsomes . In liver fibrosis it appears Ezh2 represses the Wnt antagonist Dickkopf-related protein 1 (DKK1) . This disparity likely reflects the end target organ. We have also seen alterations in Ezh2, and these mediate increases in tissue inhibitor of metalloproteinases 1 (TIMP-1) in monocytes from SSc patients, thus promoting a pro-fibrotic environment . There are multiple other histone methyltransferases that mediate specific marks in the histones, but none of these have been examined in relation to SSc. Long non-coding RNAs Recent estimates suggest that protein-coding genes comprise only 1–2% of the genome; the rest is non-coding. Non-coding RNAs longer than 200 nt in length are called long non-coding RNAs (lncRNAs). It is now known that lncRNAs can be transcribed from every locus of the human genome and can be in sense or antisense form . Sense lncRNAs overlap one or more exons of a coding gene and antisense transcripts have complementarity to the opposite strand. Compared with miRNAs, their functions are still relatively obscure. In SSc the lncRNA TSIX is dysregulated . TSIX is thought to be important in the silencing of X-linked genes in X-chromosome inactivation and may accomplish this by altering polycomb repressive complex 2 (PRC2). Silencing of TSIX reduced collagen I levels in SSc fibroblasts and this appeared to occur through collagen mRNA stabilization . TGF-β1 also induced the expression of TSIX . Because study of the function of lncRNAs is still in its infancy, it is currently hard to work this out. It has been proposed that they act as endogenous miRNA sponges . miRNAs miRNAs are a class of small non-coding RNAs that are usually between 18 and 22 nt long and are generated from longer precursors. They mediate their effects through binding to the 3′-untranslated region (3′UTR) of their target mRNAs leading to destabilization and repression . One miRNA can theoretically target hundreds of mRNAs due to the promiscuity of binding, and thus target identification has been a thorn in the side for researchers in this area . miRNAs are encoded in the genome as intronic miRNAs or intergenic miRNAs, transcribed under the control of their own promoter. miRNAs have now been demonstrated to regulate nearly all cellular processes and can themselves be induced or repressed by the local microenvironment. In terms of fibrosis in SSc, they can be either pro- or anti-fibrotic in nature and the balance between the pro- and anti-fibrotic miRNAs is important in determing whether the final output is fibrotic or not. It has been shown that miR21 is an important profibrogenic miRNA (fibromiR) . miR21 has been shown to be highly elevated in SSc skin biopsies and dermal fibroblasts . It was also found to be highly up-regulated upon TGF-β1 stimulation and found mechanistically to target Smad7 , which is the inhibitory Smad that is used to negatively regulate TGF-β signalling. Thus a reduction in Smad7 would lead to less negative feedback and enhanced unabated TGF-β signalling in these cells, leading to enhanced ECM deposition. miRNA29a appears to be a critical miRNA in all forms of fibrosis  and is now known to be dysregulated in liver  and kidney fibrosis . In SSc there is a much reduced expression of miR29a, and this was also the case in the bleomycin model of skin fibrosis . Incubation with PDGF also reduced miR29a expression levels. We found that miR29a modulates the regulator of matrix breakdown, TIMP-1, which leads to net collagen deposition . It targets a multitude of different collagens and so is considered a master regulator of fibrosis. Delivery of viral miR29a to mice with experimentally induced liver fibrosis diminished the fibrosis . Another miRNA, miR30b, is significantly reduced in SSc . It was found that this miR targets PDGF receptor (PDGFR)  and it is known that PDGF is critical in fibrosis. It has also been demonstrated that the miR let7a is significantly down-regulated in SSc . Importantly, it was demonstrated that the direct target of let7a in dermal fibroblasts was collagen 1A; using 3′UTR luciferase assays  and systemic administration of a let7a mimic in vivo in an animal model of fibrosis, it was demonstrated that skin fibrosis was attenuated . Furthermore, let7g has also been found to be dysregulated in SSc fibroblasts . Honda et al.  recently described the down-regulation of miR150 in SSc myofibroblasts and that the target is integrin β3; this integrin is important in the activation and availability of TGF-β and thus leads to enhanced TGF-β activity and Smad3 activation. Recently, in the bleomycin model of fibrosis, miR155 KO mice were protected from fibrosis compared with wild-type mice. Remarkably, topical treatment with a miR155 antagomir attenuated skin fibrosis also, suggesting this as a therapeutic approach . miR155 is highly elevated in SSc, but it does not appear to change upon TGF-β treatment ; however, a recent report suggests that it activates the inflammasome leading to fibrosis . miRNA5196 has recently been shown to be dysregulated in SSc and to target Fra-2, a central transcription factor in fibrosis , and miR4458 was recently described to be dysregulated in SSc and to target collagen 1 directly . Targeting miRNAs Using miRNA as therapeutics was achieved in vivo over 10 years ago using synthetic antagomirs . This included the use of oligonucleotide antagomirs that were chemically modified with a cholesterol on the oligo to silence in vivo miR122 . Anti-miRNAs represss the miRNA resulting in a derepression of the mRNA targets. The anti-miRNAs are chemically modified to make them more stable as they would easily be broken down under the influence of endogenous RNAses. Most common modifications of miRNAs are 2′-sugar modifications or locked nucleic acid; this forms a bicyclic nucleotide, increasing stability. Because the introduction of the synthetic miRNA will affect multiple genes and since miRNAs target multiple genes in a pathway, this could lead to a major effect on a given pathway with just one miRNA. In an animal model of lung fibrosis, restoration of diminished miR29a resulted in much reduced fibrosis . The injection of an miR29a mimic blunted clinical fibrosis and histological markers and reduction of its direct targets, collagen 1A1 and collagen 3A1 . Miragen are currently taking a synthetic miR29b mimic into clinical trials for SSc (www.miragen.com). The miR29 restitution study demonstrated clear feasibility of restoring miRNA function and reducing fibrosis. The delivery of miRNA whether, mimics or anti-miRNAs lipid based vehicles, cationic polymers and viral systems are all ways to deliver the cargo. Adenoviral vector systems are useful as they have the feature of cell tropism without leading to a significant inflammatory response. Viral vector systems of delivery have these unique properties and adeno-associated viruses appear even more efficacious . Whichever system is employed for delivery it must be robust, hit the target and not induce a host inflammatory response. DNA methylation Methylation of DNA occurs on the fifth carbon of cytosine in the DNA and on cytosine phosphoguanine dinucleotides, called CpG islands . In the great majority of cases, hypermethylation results in gene repression and hypomethylation results in elevated gene expression. DNA methylation is a relatively stable and heritable epigenetic mark. The enzymes that catalyse the addition of the methyl group are the DNA methyltransferases (DNMTs), which includes DNMT1, DNMT3a and DNMT3b. Although in other fibrotic diseases major genome-wide methylation studies have been common, only one has been undertaken in SSc fibroblasts . In this study a genome-wide methylation study of both limited and diffuse SSc fibroblasts was undertaken and 118 hypomethyated genes were discovered. One hypomethylated gene that was found in SSc was ITGA9 . ITGA9 is an α-integrin that interestingly is a receptor for thrombospondin-1, which promotes angiogenesis  (Table 1). This could provide a link between altered methylation and dysregulated integrin and angiogenesis. In SSc, ten–eleven translocation methylcytosine dioxygenase 1 (TET1), the enzyme responsible for demethylation, appears perturbed and is regulated by hypoxia in SSc [53, 54]. There also appears to be a trend towards overall global hypomethylation , although global methylation analysis is now of limited value due to gene-specific methylation changes. Table 1 Methylated genes in SSc dermal fibroblasts Gene Methylation status Fli-1 Hypermethylated DKK, SFRP-1 Hypermethylated ITGA9 Hypomethylated ADAM12 Hypomethylated PAX9 Hypomethylated Gene Methylation status Fli-1 Hypermethylated DKK, SFRP-1 Hypermethylated ITGA9 Hypomethylated ADAM12 Hypomethylated PAX9 Hypomethylated Table 1 Methylated genes in SSc dermal fibroblasts Gene Methylation status Fli-1 Hypermethylated DKK, SFRP-1 Hypermethylated ITGA9 Hypomethylated ADAM12 Hypomethylated PAX9 Hypomethylated Gene Methylation status Fli-1 Hypermethylated DKK, SFRP-1 Hypermethylated ITGA9 Hypomethylated ADAM12 Hypomethylated PAX9 Hypomethylated The endogenous Wnt extracellular antagonists are down-regulated due to promoter hypermethylation . Incubation of the SSc dermal fibroblasts with the demethylating agent 5-axa-2′deoxycytidine resulted in reversal of the Wnt antagonist secreted frizzled-related protein 1 (sFRP-1) and reduced collagen . Friend leukaemia integration 1 (Fli-1) is also hypermethylated in SSc dermal fibroblasts leading to repression and enhanced collagen . We have also found hypermethyation of miR135b, and incubation of dermal fibroblasts with decatabine reduced collagen levels in dermal fibroblasts from SSc patients . This all suggests that decatabine may be a promising agent in SSc as it likely targets multiple pathways simultaneously and also reverses collagen expression in keloid fibroblasts . Guadecitabine stabilizes dinucleotides composed of deoxyguanosine and decitabine and has shown promising results in acute myeloid leukaemia . It has also been shown that the transcription factor Fli-1 is hypermethylated in SSc fibroblasts , which leads to its repression in an specificity protein-1-dependent pathway. Thus as a negative regulator of collagen, repressed Fli-1 leads to enhanced collagen levels, and Fli-1 is consistently repressed in SSc . This is accompanied by elevated DNMT1 levels in SSc fibroblasts . Interestingly, hypermethylation of chromosome 8 open reading frame 4 (c8orf4) in SSc fibroblasts directly represses cyclooxygenase-2  and thus its product, prostaglandin E2, which imparts a pro-fibrotic phenotype. Methylation of DNA is recognized by methyl binding domain (MBD) proteins, which contain a domain that recognizes methylation that mediates gene repression. The methyl binding domain proteins consist of MBD1, MBD2, MBD4 and methyl cap binding protein 2 (MeCP2). We have found elevated levels of MeCP2 in SSc dermal fibroblasts and this can be induced upon stimulation with TGF-β1  suggesting it is important in fibrosis. Indeed, in culture SSc fibroblasts remain myofibroblasts even in the absence of exogenous growth factors or fibrotic stimuli for multiple passages coincident with MeCP2 expression, and interestingly there is a small nucleotide polymorphism in MeCP2 associated with diffuse SSc . Conclusions It is now widely appreciated that epigenetics plays a key role in many diseases including SSc. The myofibroblast is the chief cell type associated with fibrosis in SSc, and multiple epigenetic aberrations have been found associated with this cell, including histone code changes, miRNA alterations and DNA methylation changes. Although DNA methylation is the most widely studied epigenetic mark, in SSc few studies have examined this in major detail. We, and others, have found that compounds that demethylate DNA reduced collagen and ECM deposition [55, 56], and this suggests that compounds such as decitibine may be useful; they are currently licensed for myelodysplastic syndrome. The toxicity of such DNMT inhibitors appears tolerable. Further studies on DNA methylation of a gene-specific nature will help us uncover the role of DNA methylation in myofibroblast activation. More studies are ongoing into miRNAs and how they are affected in the disease. 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Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Rheumatology – Oxford University Press
Published: Mar 22, 2018
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