Chemical compounds that are added to single genes can regulate their activity; these modifications are known as epigenetic changes. The epigenome. The molecular mechanisms responsible for imprinting are defined by the inheritance of epigenetic tags (see FAQ 7) from cell generation to cell generation and. Three main epigenetic mechanisms have been described including noncoding RNA species, DNA methylation, and histone modification.
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To receive news and publication updates for Mediators of Eigenetik, enter your email address in the box below. This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Systemic inflammatory rheumatic diseases are considered as autoimmune diseases, meaning that the balance between recognition of pathogens and avoidance adaalh self-attack is impaired and the immune system attacks and destroys dpigenetik own healthy tissue.
Although biologic drugs have largely improved the outcome in many patients, such drugs still pose significant problems and fail to provide a solution to all patients. The reversible nature of epigenetic mechanisms offers a new class of drugs that modulate the immune system and inflammation.
In fact, epigenetic drugs are already in use in some types of cancer or cardiovascular diseases. Therefore, epigenetic-based therapeutics that control autoimmunity and chronic inflammatory process have broad implications for the pathogenesis, diagnosis, and management of rheumatic diseases. This review summarises the latest information about potential therapeutic application of epigenetic modification in targeting immune abnormalities and inflammation of rheumatic diseases.
Systemic autoimmune rheumatic diseases are characterised by pain and chronic joint inflammation. There are more than different conditions that are labelled as rheumatic diseases including rheumatic arthritis, systemic sclerosis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, and Sjogren syndrome. Moreover, autoimmune rheumatic diseases share many common features, which makes them difficult to differentiate within the epigenetkk.
Indeed, up to 50 percent of patients with autoimmune rheumatic diseases cannot be easily categorised with a specific disorder in the first 12 months of follow-up [ 1 ]. Immune cells play a key role in inflammation due to involvement in initiation and maintenance of the chronic inflammatory stages. Monocytes are also responsible for the production of inflammatory mediators including reactive oxygen species Eligenetik and cyclooxygenase-2 COX-2 [ 3 ]. COX-2 is a key enzyme in prostaglandins biosynthesis driving the inflammatory response.
Monocytes can produce chemokines which attract T and Qdalah cells for the secretion of proinflammatory cytokines.
Activated B cells are able to present autoantigens and produce autoantibodies maintaining the inflammatory process leading to tissue destruction. The presence of autoantibodies is a hallmark of autoimmune rheumatic diseases [ 4 ]. Th17 cells are characterised by production of IL Fibroblast-like synoviocytes FLS located inside joints in the synovium also play epigenegik key role in pathogenesis of rheumatic diseases due to their production of proinflammatory cytokines, adhesion molecules, and matrix proteases contributing to cartilage destruction.
Rheumatoid FLS develop a unique autoaggressive phenotype that increases invasiveness into the extracellular matrix, promotes inflammatory cell recruitment, and elevates production of COX Although COX-inhibitors adallah to reduced synthesis of prostaglandins at the site of inflammation, suppression of gastrointestinal or renal prostaglandins synthesis is associated with mechanism-based toxicities.
This limits the usefulness of these otherwise potent drugs. In addition, COX-2 inhibitors have been found to increase the risk of epitenetik infarction. Thus, finding new agents which will specifically block inflammation may provide therapeutic opportunities in immune-mediated rheumatic diseases.
Epigenetics is defined as reversible and heritable changes in gene function without alteration of the underlying DNA sequence itself [ 6 ].
Epigenetic mechanisms are sensitive to external stimuli, bridging the gap between environmental and genetic factors. In particular, monozygotic MZ twins do not show complete concordance for many complex diseases. MZ discordance rates for autoimmune diseases are 20—80 percent, indicating a substantial role of epigenetic factors in the development of these disorders [ 78 ]. These molecules are constitutively produced by a variety of immune cells under chronic inflammatory conditions, which consequently leads to the development of many diseases epigenerik cancer, cardiovascular diseases, or autoimmune rheumatic disorders.
Three main epigenetic mechanisms have been described including noncoding RNA species, DNA methylation, and histone modification. It is known that miRNAs can act as a fine-tuner of gene expression and can negatively regulate approximately 30 percent of human protein-coding genes [ 10 ].
In addition, miRNAs are attractive as potential biomarkers. Some of miRNAs have been already tested in preclinical studies that aimed to treat cancer including lung, prostate, or leukemia [ 11 ]. Recent phase I clinical trial has also tested the drug called MRX Thus, MRX34 is widely tested in solid tumours and hematological malignancies [ 9 ].
Many studies have also shown the role of lncRNA in diverse cellular processes. However, the exact functional roles and mechanisms of lncRNAs are still unclear.
The insertion of methyl group to cytosine at the carbon 5 position leads to structural changes in chromatin and is mostly associated with gene epigdnetik. In humans, methylation epigendtik occurs when cytosine is followed by guanine and is linked with phosphate called CpG islands. Approximately 1 percent of the genome consists of CpG islands [ 11 ]. Also, it is reported that roughly 60—70 percent of human genes are linked to promoter CpG islands which suggests that methylation of CpG island is an important regulatory mechanism of gene expression [ 12 ].
It has been shown that vitamin B12 rich diet B vitamins acted as methyl donors in agouti mouse model prevented from development of inflammation mediated diabetes and cancer. In contrast, mice which did not receive vitamin B were predisposed for these diseases [ 14 ]. Therefore, methylation plays a key role in physiological conditions and the alteration in DNA methylation signature can have impact on disease development.
This drug has been already used in phase III randomised, controlled trial to treat myelodysplastic syndrome and leukemia [ 15 ]. DNA hydroxymethylation is also epigenetic modification mediated by Ten-Eleven Translocation TET family proteins which were discovered relatively recently [ 18 ].
TET enzymes are dioxygenases capable of oxidizing the methyl group of 5-methylcytosine 5mC and converting 5mC into 5-hydroxymethylcytosine 5hmCwhich results in DNA demethylation. Interestingly, treatment with methotrexate partially reduces the DNA hydroxymethylation level. Indirect TET inhibition induced by AGI compound leads to growth suppression and promotes differentiation of glioma cells [ 20 ]. Similarly, HMS inhibitor limits the growth of acute myeloid leukemia cells suggesting potential therapeutic application of TET inhibitors in cancer and also in rheumatic diseases [ 21 ].
Another epigenetic phenomenon is histone modification.
This modification alters the electrostatic charge of the histones resulting in conformational changes in protein binding sites and facilitating or blocking DNA accessibility. Histone modifications can be mostly represented by acetylation, methylation, phosphorylation, ubiquitination, ribosylation, citrullination, biotinylation, and sumoylation of histone N-terminal tail domains and also core domains [ 22 ].
It is believed that the histone acetylation is usually associated with increased binding of transcription factors to nucleosomal DNA and facilitates transcription initiation, whereas histone methylation can either activate or repress gene expression. Acetylation removes the positive charge on the histones and reduces the interaction between histones and negatively charged phosphate groups on DNA [ 23 ].
Therefore, the condensed heterochromatin is transformed into a more relaxed euchromatin that is associated with greater levels of gene transcription. HDACs catalyse the removal of acetyl group from lysine residue. This drug was the first histone deacetylase inhibitor to be approved by FDA to treat cutaneous T cell lymphoma with substantial response rates over 30 percent in patients [ 24 ].
Unlike in the cancer field, there is still no epigenetics-based drug on the market to treat rheumatic disorders. Finding new agents is greatly needed, because the economic burden of rheumatic diseases is substantial.
Their cost is estimated at more than billion Euros per year in Europe and they are the most expensive of all diseases for the European health care systems [ 25 ]. However, it is a chicken or egg dilemma and it needs to be further investigated to find out whether inflammation triggers epigenetic changes or epigenetic alteration drives inflammation.
Epigenetic mechanisms, which modify immune cells and fibroblasts in rheumatic diseases, are depicted in Figure 1. RA is a chronic autoimmune inflammatory condition which is characterised by an influx of inflammatory cells from the blood stream into the synovial membrane or synovial fluid. Such influx of immune cells producing inflammatory cytokines results in progressive erosion of articular cartilage.
Phagocytes, B cells, and T cells are the most prominent cells in the rheumatoid synovium. Macrophages along with granulocytes are an important source of proinflammatory cytokines, chemokines, and reactive oxygen species ROS that accompany inflammatory processes [ 4 ]. On the other hand, antigen-specific B cells are involved in autoantigens presentation to T cells and in production of autoantibodies, which mediates in joint destruction.
In addition, the presence of ectopic follicular structures in chronically inflamed tissues resembling germinal centres provides strong evidence of ongoing immune reactions [ 26 ]. In contrast, Zhang et al.
Epigenetics – Wikipedia
Emerging evidence revealed that lncRNAs have various expression in autoimmune diseases. Similarly, Song et al. DNA methylation pattern is also impaired in RA affecting immune-related genes and consequently influencing immune responses. It is known that IL-6 plays a pivotal role in chronic inflammation in autoimmune diseases [ 35 ]. Another group has identified that the promoter of anti-inflammatory cytokine IL is hypermethylated in four different regions of CpG site [ 36 ].
Epigenetics: Fundamentals, History, and Examples | What is Epigenetics?
It has been also found that alteration in histone modification can contribute to RA development. This consequently leads to proinflammatory genes expression including IL-6 and IL Indeed, the level of histone H3 acetylation in the IL-6 promoter is significantly elevated in RA synoviocytes resulting in enhanced IL-6 secretion and joint destruction [ 38 ].
Surprisingly, treatment with curcumin abrogated H3 acetylation and reduced IL-6 secretion which suggests that epigenetic mechanisms are implicated in adalzh RA pathogenesis. Systemic sclerosis SSc is an spigenetik connective tissue disease characterised by autoimmunity, vascular abnormalities, and fibrosis via accumulation of extracellular matrix Epienetik proteins. Uncontrolled fibrosis progression often results in dysfunction of the affected organs and consequently leads to premature death in SSc patients [ 39 ].
It has been zdalah that the family of miRNA plays a pivotal role in SSc skin fibrosis by targeting collagen expression [ 1920 ]. In addition, we have shown that SSc fibroblasts are able to reverse fibrotic phenotype following miRNA transfection. BAFF plays a central role in the survival and homeostasis of B cells and plasma cells. These data suggest that demethylation of CD11a regulatory elements and subsequent CD11a overexpression in T cells may mediate immunological abnormalities and fibrotic processes in SSc.
This indicates that specific targeting DNA methylation may represent a novel therapeutic approach for the treatment of SSc. Another hallmark of SSc is perivascular infiltration of immune cells, mainly monocytes, which are the first immune cells to infiltrate the SSc skin.
Interestingly, we have also shown that epigenetic modification induced by DZNep histone methyltransferases or apicidin inhibitor of histone acetylases in SSc monocytes can modulate TIMP-1 expression and subsequently fibroblasts transdifferentiation [ 44 ]. Another study has shown that global H4 but not Epigenetil acetylation of SSc B cells was positively correlated with disease activity and that the expression of HDAC2 adlaah was negatively correlated with skin thickness [ 45 ].
This clearly indicates that epigenetic alteration plays an ada,ah role in the pathogenesis of SSc. Psoriatic Arthritis PsA is a chronic inflammatory skin disease with unknown etiology.
The interactions between genetics and the environmental factors in PsA are still not well defined. The disease is characterised by abnormal proliferation and differentiation of keratinocytes. Wpigenetik addition, infiltration of immune cells which secrete high level of various immune-regulated inflammatory cytokines and chemokines is observed in PsA.
Recently, imbalance in epigenetic networks has been indicated to be an important element in epivenetik development. Several studies have shown that differentially expressed miRNAs levels play a role in psoriasis pathogenesis.
In particular, it has been reported that miRNA expression is downregulated in psoriatic lesion. Another group identified that miRNAa is also dysregulated in psoriatic lesions.