|Year : 2018 | Volume
| Issue : 3 | Page : 723-729
Epigenetics and autoimmunity
Sabery A Shoeib1, Alaa E Abd El Hamid1, Salah M.S Abozied2
1 Department of Internal Medicine, Haematology and BMT Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Zefta Hospital, Zefta, Gharbia, Egypt
|Date of Submission||01-Oct-2016|
|Date of Acceptance||11-Dec-2016|
|Date of Web Publication||31-Dec-2018|
Salah M.S Abozied
Ajizy, Tanta, Gharbiya
Source of Support: None, Conflict of Interest: None
The aim of the study was to review epigenetics and its role in the evolution and treatment of autoimmune disorders.
Data were obtained from Medline databases (PubMed, Medscape, and Science Direct) and from materials available on the Internet from 2003 to 2016.
The initial search presented 100 articles, of which 30 met the inclusion criteria. The articles studied the role of epigenetics in the pathogenesis and treatment of autoimmune disorders.
A special search was carried out on Medline with keywords (epigenetics and autoimmune) in the papers, and extraction was made, including assessment of the quality and validity of papers that met with the prior criteria that describe the role of epigenetics in autoimmunity.
Each study was reviewed independently; the obtained data were translated into the language of the researcher and have been presented in sections throughout the article.
The studies define epigenetics as changes in gene expression without changes in the DNA itself. Epigenetic regulation was achieved through DNA methylation, histone modification, and microRNA interference. Deregulations in epigenetic mechanisms present an important pathway toward the development of autoimmune disorders. DNA-demethylating and histone-deacetylating agents are the first era of drugs directed at treating epigenetic deregulations with significant success rates.
Unlike genetics, the reversible nature of epigenetics makes them highly attractive targets for cancer therapies. DNA-demethylating and histone-deacetylating agents are the first drugs directed at treating epigenetic deregulations. Understanding epigenetic mechanisms will be helpful in introducing new lines of treatment.
Keywords: autoimmune diseases, epigenetic therapy, epigenetics, genetics
|How to cite this article:|
Shoeib SA, Abd El Hamid AE, Abozied SM. Epigenetics and autoimmunity. Menoufia Med J 2018;31:723-9
| Introduction|| |
Autoimmune disorders comprise a wide range of genetically complex diseases. Genetics is only one aspect of the diseases that does not reflect the influence of environment, sex, or aging. Epigenetics, the control of gene packaging and expression independent of alterations in the DNA sequence, is providing directions linking genetics and environmental factors. The definition of epigenetics is broad and has been modified over the years; it is currently generally accepted to refer to changes in gene activity independent of the primary DNA sequence.
Epigenetic mechanisms such as DNA methylation, histone modification, nucleosome positioning, and microRNAs (miRNAs) are essential to carry out key functions in the regulation of gene expression, whether this is to activate or repress it, and are a window to understanding the possible mechanisms involved in the pathogenesis of autoimmune diseases. These mechanisms play an essential role in the regulation of gene and miRNA expression, DNA–protein interactions, cell differentiation, embryogenesis, X-chromosome inactivation, and genomic imprinting.
DNA methylation of cytosine in mammalian cells occurs through the action of 5-methylcytosine DNA methyltransferases (DNMTs), which transfer a methyl group from a methyl group donor, S-adenosylmethionine, to the fifth carbon of the cytosine residues, converting them to 5-methylcytosines. Therefore, a dysfunction of the normal state DNA methylation would lead to disease.
Methylation of cytosine residues is mediated by an evolutionarily divergent set of DNMTs; this family of enzymes has five members: DNMT1, DNMT2, DNMT3a, DNMT3b, and DNMT3L. DNMT1 recognizes hemimethylated cytosines and functions as the maintenance methyltransferase enzyme, copying epigenetic information during DNA replication in the S phase of the cell cycle to new DNA strands, whereas DNMT3a and DNMT3b set the methylation code de novo. DNMT2 mediates RNA methylation. Demethylation of DNA is a long-debated topic; it now appears that both active and passive demethylation occurs.
The basic repeating unit of chromatin is the nucleosome, in which 147 base pairs of negatively charged DNA wrap 1.65 times around a highly positively charged histone protein octamer. Histones are conserved proteins that package and organize DNA. These proteins can be grouped in core histones (H2A, H2B, H3, and H4) and linker histones (H1 and H5). Core histones have long N-terminal tails protruding from the nucleosome, which can undergo post-translational modifications that alter their interaction with DNA and nuclear proteins. The standard way of reporting those modifications is by naming the histone, followed by the amino acid, and the modification. For example, H3K4me1 would denote single methylation (me1) of lysine 4 (k4) on histone 3 (H3). Research has shown a strong relation between covalent histone modifications and gene expression.
Histones suffer some post-translational modifications such as lysine acetylation, and methylation, phosphorylation, ubiquitination, and ADP ribosylation. Histone modifications play an important role in transcriptional regulation, DNA repair, DNA replication, and chromosome condensation.
Acetylation/deacetylation and methylation/demethylation appear to be of most importance in regulating gene expression. Acetylation (through the action of histone acetyltransferases) of selected lysine residues in the tails of nucleosomal histones removes the positive charge on the lysine amino group that is acetylated, loosening the interaction between DNA and the histone and preventing chromatin from folding into the 30 nm fiber; this typically promotes gene expression.
Nucleosomes are a complex form of DNA packaged by histones. There are nucleosome positioning patterns that play an important role in transcriptional regulation. Depending on how close nucleosomes are to transcription start sites, they may block the activators' and transcription factors' access to the DNA strand, thus inhibiting elongation of the transcripts. Active gene promoters have a nucleosome-free region at the 5' and 3' untranslated region to facilitate the assembly and disassembly of the transcription machinery.
MiRNAs are tightly regulated by a range of mechanisms involving protein–protein and protein–RNA interactions affecting primary miRNA transcription, miRNA biogenesis, function, and degradation. These processes are essential for the specific functions of miRNAs, as alterations are commonly associated with different disease states. Abundance of miRNA expression could result from the following: (i) the transcription of the miRNA host gene, (ii) the processing of the transcribed pri-miRNA into the mature miRNA, and (iii) the stability of the miRNA.
MiRNAs regulate several biological processes such as apoptosis, insulin secretion, lipid metabolism, stem cell differentiation, heart development, muscle differentiation, cardiomyocyte hypertrophy, antigen presentation, and aging.
By controlling different stages of miRNA biogenesis and localization, degradation, and activity, RNA-binding proteins (RBPs) function as key components in the determination of miRNA function. Alteration of RBP function in any of the crucial steps of the miRNA pathway can lead to impairment. Similar to miRNA, RBPs can regulate mRNA stability and translation. They bind to mRNAs and facilitate or counteract miRISC (RNA-induced silencing complex) activity.
| Materials and Methods|| |
We reviewed papers on the role of epigenetics in autoimmunity from Medline databases (PubMed, Medscape, and Science Direct) and also from materials available on the Internet. We used genetics/epigenomics/epigenetic mechanisms and autoimmune disorders as searching terms. In addition, we examined references from the specialist databases and reference lists in relevant publications and published reports. The search was performed in the electronic databases from 2003 to 2016.
All of the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria.
Inclusion criteria of the published studies were as follows:
Published in English language.
Published in peer-reviewed journals.
Focused on the role of epigenetics in autoimmune disorders.
Discussed epigenetic mechanisms and its role in the evolution and treatment of autoimmune disorders.
If a study had several publications on certain aspects we used the latest publication giving the most relevant data.
If the studies did not fulfill the above criteria, they were excluded – for example, reports without peer-review and studies not focused on the role of epigenetics in autoimmunity. The analyzed publications were evaluated according to evidence-based medicine criteria using the classification of the US Preventive Services Task Force, which include the following:
Level I: Evidence obtained from at least one properly designed randomized controlled trial.
Level II-1: Evidence obtained from well-designed controlled trials without randomization.
Level II-2: Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group.
Level II-3: Evidence obtained from multiple time series with or without the intervention. Significant results in uncontrolled trials might also be regarded as this type of evidence.
Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
The quality of all studies was assessed. Important factors included study design, attainment of ethical approval, and evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.
Each study was reviewed independently; the obtained data were translated into the language of the researcher and have been presented in sections throughout the article.
| Results|| |
Autoimmune diseases are a complex group of diseases. Genetic background confers susceptibility to or protection from disease onset, but it is neither sufficient nor causative for disease development. Each autoimmune disease involves at least two major players, the immune system, which is the effector of the autoimmune damage, and the target organ, which can have variable degrees of resistance to autoimmune damage. Epigenetic modifications to either the immune system or the target organ could play a role in disease development.
Epigenetics is a dynamic process as the reversible nature of epigenetic control allows for changes that can open silenced genes to become potentially active genes and back. Moreover, it can convert large regions of chromatin from euchromatin to heterochromatin and back. Epigenetic mechanisms are essential to carry out key functions in the regulation of gene expression and are a window to understand the possible mechanisms involved in the pathogenesis of autoimmune diseases. These mechanisms increase the prospects for controlling or preventing autoimmune diseases through the use of drugs that target the epigenetic pathways.
Epigenetic therapies are an important target for the treatment or prevention of autoimmune diseases.
Epigenetic therapies for systemic lupus erythematosus
American College of Rheumatology meeting abstract reported that valproic acid may prevent skin disease and reduce kidney disease severity in murine lupus. Histone deacetylase inhibitors (HDACis) such as suberoylanilidehydroxamic acid and trichostatin A (TSA) have also been shown to ameliorate systemic lupus erythematosus (SLE) disease (e.g., nephritis) in mice.
Epigenetic therapies for rheumatoid arthritis
DNMT inhibitors such as 5-azaC were used to treat normal synovial fibroblasts, and this reproduced reumatoid arthritis synovial fibroblasts (RASF) phenotype. TSA and nicotinamide, both HDACis, were separately used to reduce tumor necrosis factor-α, which in turn reduces interleukin-6 expression in macrophages isolated from the peripheral mononuclear cells of rheumatoid arthritis (RA) patients. Others have shown that targeting HDACs, using HDACi such as valproic acid, can mitigate the severity of murine chronic inflammatory arthritis, in part by improving regulatory T-cell function. Another promising study silenced SIRT1 and promoted apoptosis in RASFs from synovial tissues and cells from RA patients.
Epigenetic therapies for systemic sclerosis
This is solid evidence that portrays the antifibrotic effect of DNMT inhibitors. TSA primarily reduces all transcripts of HDACs and is especially potent toward the inhibition of HDAC7, possibly making it a specific and targetable component of systemic sclerosis (SSc) pathogenesis. HDAC inhibitors can repress collagen suppressor gene FL11 and restore normal collage expression in SSc fibroblasts. The promoter of FL11 is hypermethylated in SSc fibroblasts, which leads to the suppression of its transcription; therefore, incubating it with 5-aza increases its transcription and decreases the release of collagen.
Epigenetic therapies for type 1 diabetes
Few research studies have been carried out on testing epigenetic drugs on type 1 diabetes (T1D) models. There was a study that inhibited class I and class II HDACs with TSA, which led to an enrichment of endocrine progenitor cells and β cells. In contrast, inhibiting class I HDACs with valproic acid instead enhances endocrine progenitor and α-cell pool.
Epigenetic therapies for multiple sclerosis
Histone deacetylases inhibitor, such as TSA, has reduced spinal cord inflammation, demyelination, and neuronal and axonal loss in experimental autoimmune encephalomyelitis models, and thus it has potential as a treatment option for multiple sclerosis (MS). Citrullinated histone is a target in epigenetic intervention in MS and RA. They postulate that shielding citrullinated histone epitopes, which play a large role in NET formation, can help prevent the intensification of the inflammatory response in MS and other inflammatory diseases.
| Discussion|| |
Epigenetics was defined by Conrad Waddington in the early 1940s as the branch of biology that studies the causal interactions between genes and their products, which bring the phenotype into being.
Although the definition of epigenetics is broad and has been modified over the years, it is currently generally accepted to refer to changes in gene activity independent of the primary DNA sequence. In some definitions, only the modification of activity states inherited across cell division is considered. Thus, independent of the genotype, different epigenetic profiles may result in different phenotypes.
Studies highlight that epigenetic mechanisms such as DNA methylation and histone modifications regulate gene expression levels and provide an alternative mechanism for modulating gene function and genetic changes. Robust analysis of these epigenetic mechanisms will not only yield useful biomarkers for the diagnosis and prognosis of autoimmune disorders but also lead to the identification of molecular targets for the manipulation of autoimmune diseases.
Stimuli induce epigenetic changes that lead to autoimmunity
There are many stimuli that affect epigenetics, both external (e.g., diet, exposure to sunlight, environmental chemicals, toxins, retroviruses, and drugs/pharmaceuticals), and internal (e.g., aging, stress, exercise, and sex hormones).
Role of epigenetics modifications on autoimmune diseases
Systemic lupus erythematosus
The development of a systemic involvement and clinical manifestation probably require the presence of lupus susceptibility genes. Studies have uncovered the importance of DNA hypomethylation in SLE etiology, and in particular it has been suggested that this phenomenon may affect the structure of T-cell chromatin, resulting in cellular hyperactivity. Changes in DNA methylation are regulated by the extracellular signal-regulated kinase signaling pathway, and this pathway is reduced in murine T-cells causing a decreased expression of DNMT1 and an overexpression of methylation-sensitive autoimmunity genes, similar to T-cells in human SLE.
During apoptosis, the nucleosome is modified, thereby creating more immunogenic epitopes. Subsequently, epitope spreading will lead to the formation of autoantibodies against unmodified chromatin components. These apoptotic nucleosomes will generate autoimmunogenicity that will cause the activation of antigen-presenting cells and autoantibody production with a subsequent inflammatory response.
The dysregulated expression profile of microRNAs plays an important role in the pathogenesis of SLE. In the last decades, several independent profiling studies on immune-cell-derived or circulating miRNA expression reported significant differences between SLE patients and healthy controls, which provide useful information for understanding SLE pathogenesis and the development of biomarkers for diagnosis, prognosis, and novel therapeutic targets.
It has been proposed that RASF or the mononuclear cell fraction extracted from whole blood has a major role in the initiation and perpetuation of RA, possibly through decreased global DNA methylation or hypomethylation of CpG islands in LINE-1 promoter. Unmethylated CpG islands within interleukin-6 promoter gene in monocytes have been associated with a local hyperactivation of the inflammation circuit. Histone modifications in RA have been less well studied, but studies reported that HDAC1 expression was increased in response to tumor necrosis factor-α supplementation in RA synovial fibroblasts.
Hypomethylation of CD4+ T-cells, driven at least in part by the downregulation of DNA methyltransferases, contribute significantly to the overexpression of various genes important to disease progression. Demethylation of the ordinarily quiescent copy of CD40L on the female Barr body has been described, giving a hint about the female predominance of the disease. Studies identified a reduced expression of FL1, a transcription factor that inhibits collagen production with an inverse correlation between FL1 expression and type I collagen production in cultured fibroblasts. An epigenetic regulation of FL1 is indirectly suggested by the presence of CpG islands in FL1 promoter that can be methylated and bound to specific regulatory proteins.
Type 1 diabetes
In this autoimmune disease, in contrast to SLE and RA, there is a global hypermethylation activity caused by altered metabolism of homocysteine. Glucose and insulin levels are determinants of methylation. They alter homocysteine metabolism by increasing cell homocysteine production through its inhibition of trans-sulfuration. When there is an increase in the levels of homocysteine, methionine in the cells will be catalyzed by DNMTs in S-adenosylmethionine. This will enhance DNMT activity that will subsequently lead to increased global DNA methylation. Another recent study has shown that T1D patients have decreased DNA methylation in the insulin-like growth factor binding protein-1 that correlates with increased circulating insulin-like growth factor binding protein-1 levels and the presence of diabetic nephropathy.
Histone modifications are also among the mechanisms that cause cardiovascular complications in T1D patients. Chemical modification of the H3K4 and H3K9 has recently been found to be related to the gene expression conferred by hyperglycemia. Transient hyperglycemia promotes gene-activating epigenetic changes and signaling events critical in the development and progression of vascular complications. These epigenetic changes are H3K4 and H3K9 methylation in genes associated with vascular inflammation.
There are limited data on epigenetics of MS, but a 30% reduction was reported in the methylation rate of cytosines in CpG islands in the white matter of affected central nervous tissue compared with controls. Studies have shown that the promoter region of peptidyl arginine deiminase type II is hypomethylated. Peptidyl arginine deiminase type II plays a key role in the citrullination process of myelin basic protein. This citrullination process has important biologic effects. It promotes protein autocleavage, which increases the probability of creating new epitopes and also modulates the immune response. It is noteworthy that all miRNAs are involved in the pathogenesis of the disease. There are miRNAs that can serve as prognostic markers. Various microRNAs have been shown to differentially express in MS samples; particularly, MIR223 was found to be upregulated in MS patients compared with healthy controls.
Primary biliary cirrhosis
Data suggest a critical role of the CXCR3/chemokine system in the development of autoimmune disorders. In addition to its role in lymphocyte recruitment to tissues, CXCR3 is also implicated in the development of Th1 cells within lymph nodes; thus, hypomethylation of CXCR3 and the consequently increased expression on CD4 T-cells could promote disease progression through enhanced Th1 differentiation and increased recruitment. X-chromosome demethylation has been shown to result in increased CXCR3 expression, suggesting this could be a common mechanism that contributes to the female susceptibility to autoimmune diseases. Owing to the rapid advance of microarray and high-throughput sequencing techniques in recent years, more than 200 differentially expressed miRNAs in primary biliary cirrhosis have been detected. By collecting patient samples from different tissues including the liver, peripheral mononuclear cells, and sera, these studies demonstrate distinct spatially miRNA profiles. The authors summarize that RT-PCR verified miRNAs from these studies and list their principal gene targets and pathways they may participate, using MicroT-CDS and miRPath, respectively.
There is a reduced global DNA methylation in salivary gland epithelial cells, peripheral T-cells, and B-cells from primary Sjögren's syndrome patients when compared with healthy control biopsies. This reduction was associated to a seven-fold decrease in DNMT1 and a two-fold increase in Gadd45-α, strongly indicative of a pathogenic role for epigenetics in SS.
| Conclusion|| |
Throughout this review, we have sought to highlight the most important discoveries in epigenetic regulation, and dysregulation, of pathways involved in the development of prevalent autoimmune diseases.
The understanding of these mechanisms and the identification of target molecules are expected to lead to new classes of therapeutical molecules, coined ‘epigenetic therapies’. We foresee that only a common effort between researchers involved in human and experimental autoimmunity and the use of powerful tools such as MZ twins will soon provide fascinating developments in the relatively young field of epigenomics.
The studies looking at epigenetic control of tolerance have probably only touched the tip of the iceberg with respect to the complexity of the levels of control and likely mechanisms; however, they do provide support that this is one way in which epigenetics could affect autoimmunity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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