ReviewEpigenetic alterations in chronic disease focusing on Behçet’s disease: Review
Introduction
While most cells have the same DNA sequence, the activity of individual genes varies significantly between different cell types and tissues. The cytokine gene is highly compressed in structure and inactive in all tissues except lymphocyte cells, in which it is in an open conformation that simplifies transcription. The word epigenetic includes heritable alterations in gene expression that do not contain changes to the fundamental DNA sequence—a change in phenotype without a change in genotype. Epigenetics was first described in 1924 by Conrad Waddington as the subdivision of biology that researches the causal interactions between genes and their products which bring the phenotype into existence [1]. These mechanisms show a crucial role in the regulation of gene and microRNA (miRNA) expressions, DNA-protein interactions [2], cell differentiation, embryo genesis [3], X-chromosome inactivation [4], genomic imprinting, and cancer and many other medical disorders such as cardiac diseases [5], diseases of the nervous system, and rheumatic diseases [6].
The activity of genes is mostly reliant on whether they are available to transcription factors; this is vastly controlled by the dynamics of chromatin restructuring [7]. Epigenetic modifications to the chromatin play a vital role in regulating the construction of chromatin and thus the availability of DNA for transcription [8]. Some of the sites in the DNA that are transcript can be turned on or off by epigenetic changes. Moreover, it has previously been verified that environmental factors, such as diet, cigarette and alcohol use, stress, exposure to chemical carcinogens and infectious agents, sexuality, and age, affect the epigenome [9], [10]. The importance of epigenetic processes has recently motivated many scientists to work in this field of research. Epigenetic changes not only affect physiological mechanisms; the pathophysiology of many diseases is interwoven with them as well [11].
Behçet’s is an autoimmune disease that was described by Hulusi Behcet in 1937 as an inflammatory process of indefinite etiology, characterized by recurrent aphthous stomatitis, uveitis, genital ulcers, and skin lesions [12]. Although Behçet’s disease (BD) is widespread and universal in different parts of the world, it has significant local differences, with the maximum incidences in the Mediterranean, the Middle East, and the Far East, which was locally called the Silk Road. The highest prevalence of Behçet’s disease has been reported in Turkey at 421 people per 105 [13]. Also, BD in the Azari population of Iran starts in the third period of their lives and has a male predominance [14].
It seems that the disease is most common in the third decade of age. However, recently there has been an increasing frequency of the disease in children and there is no evidence of hereditary factor. Also, men are affected more than women. The intensity of the disease seems to fade away as they grow older [15]. The exact pathogenesis of Behçet’s disease has not clearly been explained. However, many studies reveal that the disease may be initiated by environmental factors such as infective agents and vitamin D deficiency [16] in patients with backgrounds of genetic susceptibility [17]. More lately, researchers have tried to explain the meaning of epigenetics to embrace all that it was supposed to convey [18]. In this paper, we will take a reasonably comprehensive definition of ‘epigenetics’ as alterations that do not include DNA base changes. It also plays an essential role in regulating tissue and signal-specific gene expression, and these are interchangeably accountable for the determination of gene expression profiles of tissues and cellular subclasses.
Section snippets
Genesis of Behcet’s disease
The cause of Behcet’s disease is still not known. A number of researches have collected proof that HLA-B51 allele, located in the MHC (major histocompatibility complex) locus on chromosome 6p, is directly related with BD in all strata along the Old Silk Road [19]. The HLA-B51 is common in BD patients, with a range of 40–80 percent in racial groups, including Turkish, Asian, and European populations along the ancient Silk Road [20]. Other genes present in the MHC locus have been researched,
Mechanisms of epigenetic modifications
The mechanisms of epigenetics are leading to changes in chromatin structure by altering its components. Scientists have found four types of epigenetic mechanisms, which are totally in hand with each other to regulate the expression of genes: DNA methylation, histone modification, non-coding RNAs (ncRNAs) [34], and chromatin remodelling are such epigenetic mechanisms that interact to express the genes. (Fig. 1) Methylation rate plays an important role in physiological conditions, and
Correlation between epigenetics and rheumatic diseases
Rheumatic diseases embrace an extensive range of conditions of incompetently characterized etiopathology, many having both genetic and environmental susceptibility causes. Inflammatory rheumatic disorders, like rheumatoid arthritis (RA) and connective tissue diseases, are accompanied by chronic inflammation that generally can be defeated by constant administration of immunosuppressive therapies [49]. Advances in molecular and genetic techniques have contributed to identification of at-risk
Rheumatoid arthritis
Rheumatoid arthritis (RA) is an enduring autoimmune disorder that predominantly affects joints. The RA fibroblast-like synoviocytes (RASFs) are dominant mediators of tissue damage via the production of a variety of disease-related molecules, containing chemokines, cytokines, and adhesion molecules [53]. Recent researches attempted to show epigenetic alterations with genetic or environmental factors for RA. In addition, global modifications in DNA methylation, promoters of particular genes, were
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disorder that can affect nearly any organ and is characterized by overexpression of autoantibodies against nuclear and/or cytoplasmic self-antigens. Some affecting genetic factors have been identified in the emergence of this disease. SLE is also more usual in women in comparison to men [64]. Several researches revealed that the presence of autoantibodies in the SLE process is associated with two major alterations—increased rate
Multiple sclerosis
Multiple sclerosis (MS) is a nervous system disease characterized by autoimmune demyelination of the myelin cover of the central nervous system (CNS), affecting about 2.5 million people in general. It damages the myelin sheath, the material that surrounds and defends the nerve cells [73]. MS is driven by dysregulated T-cells that inappropriately respond to myelin and other CNS antigens.
The prominence of epigenetics in the illustration of multiple sclerosis is also proposed by studies of the
Diabetes mellitus
Type1 diabetes (T1D) is an autoimmune disease which is generated as a result of pancreatic insulin-producing β-cells apoptosis. Genome-wide association studies (GWAS) [85] have connected immune response-related genes with an increased T1D risk, yet the underling mechanisms by which these genes increase T1D susceptibility have not been illustrated [86]. Type 2 diabetes (T2D) is a typical polygenic metabolic disease. GWAS studies have shown that more than 40 genes are associated with increased
Familial Mediterranean fever
Familial Mediterranean fever (FMF) is an autoinflammatory recessive disease characterized by recurrent attacks of fever, and the inflammation of serosal membranes that usually affects Mediterranean people—mostly Iranians, Turks, Jews, Armenians and Arabs [97]. MEFV gene on the short arm of chromosome 16 is the first identified inflammatory gene which is responsible for FMF [98]. The possible epigenetic factors such as DNA methylation, histone modifications, and non-coding RNAs, may lead to
Epigenetics and Behçet’s disease
More recent studies propose the association of epigenetic variants, predominantly DNA methylation modifications, in the pathogenesis of vasculitis. In some vasculitis, such as Behçet’s disease, particular and reversible epigenetic modifications that trigger the disease pathogenesis can vary between active and inactive disease [103]. Also, in a recent study by Yüksel et al., the epigenetic modifications of IRSs (repetitive sequences) in BD were assessed using COBRA-IRS analysis technique. In
Conclusion
Research in the last three decades revealed a complex relationship between various epigenetic pathways and pathogenesis of inflammatory diseases. BD is an autoimmune/autoinflammatory disease. Few studies have been reported on the epigenetic of BD showed the role of alterations in the methylation level of IRS elements; histone modifications such as H3K4me27 and H3K4me3; up regulation of miR-182 and miR-3591-3p; down regulation of miR-155, miR-638 and miR-4488 in the pathogenesis of the disease.
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