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      Epigenetic Changes in the Pathogenesis of Rheumatoid Arthritis

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          Abstract

          Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects about 1% of the world’s population. The etiology of RA remains unknown. It is considered to occur in the presence of genetic and environmental factors. An increasing body of evidence pinpoints that epigenetic modifications play an important role in the regulation of RA pathogenesis. Epigenetics causes heritable phenotype changes that are not determined by changes in the DNA sequence. The major epigenetic mechanisms include DNA methylation, histone proteins modifications and changes in gene expression caused by microRNAs and other non-coding RNAs. These modifications are reversible and could be modulated by diet, drugs, and other environmental factors. Specific changes in DNA methylation, histone modifications and abnormal expression of non-coding RNAs associated with RA have already been identified. This review focuses on the role of these multiple epigenetic factors in the pathogenesis and progression of the disease, not only in synovial fibroblasts, immune cells, but also in the peripheral blood of patients with RA, which clearly shows their high diagnostic potential and promising targets for therapy in the future.

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          Most cited references93

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          Histone core modifications regulating nucleosome structure and dynamics.

          Post-translational modifications of histones regulate all DNA-templated processes, including replication, transcription and repair. These modifications function as platforms for the recruitment of specific effector proteins, such as transcriptional regulators or chromatin remodellers. Recent data suggest that histone modifications also have a direct effect on nucleosomal architecture. Acetylation, methylation, phosphorylation and citrullination of the histone core may influence chromatin structure by affecting histone-histone and histone-DNA interactions, as well as the binding of histones to chaperones.
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            The alternative role of DNA methylation in splicing regulation.

            Although DNA methylation was originally thought to only affect transcription, emerging evidence shows that it also regulates alternative splicing. Exons, and especially splice sites, have higher levels of DNA methylation than flanking introns, and the splicing of about 22% of alternative exons is regulated by DNA methylation. Two different mechanisms convey DNA methylation information into the regulation of alternative splicing. The first involves modulation of the elongation rate of RNA polymerase II (Pol II) by CCCTC-binding factor (CTCF) and methyl-CpG binding protein 2 (MeCP2); the second involves the formation of a protein bridge by heterochromatin protein 1 (HP1) that recruits splicing factors onto transcribed alternative exons. These two mechanisms, however, regulate only a fraction of such events, implying that more underlying mechanisms remain to be found.
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              Synovial fibroblasts spread rheumatoid arthritis to unaffected joints.

              Active rheumatoid arthritis originates from few joints but subsequently affects the majority of joints. Thus far, the pathways of the progression of the disease are largely unknown. As rheumatoid arthritis synovial fibroblasts (RASFs) which can be found in RA synovium are key players in joint destruction and are able to migrate in vitro, we evaluated the potential of RASFs to spread the disease in vivo. To simulate the primary joint of origin, we implanted healthy human cartilage together with RASFs subcutaneously into severe combined immunodeficient (SCID) mice. At the contralateral flank, we implanted healthy cartilage without cells. RASFs showed an active movement to the naive cartilage via the vasculature independent of the site of application of RASFs into the SCID mouse, leading to a marked destruction of the target cartilage. These findings support the hypothesis that the characteristic clinical phenomenon of destructive arthritis spreading between joints is mediated, at least in part, by the transmigration of activated RASFs.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                14 June 2019
                2019
                : 10
                : 570
                Affiliations
                [1] 1Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University) , Moscow, Russia
                [2] 2Laboratory of Epigenetics, Research Centre for Medical Genetics , Moscow, Russia
                [3] 3Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University) , Moscow, Russia
                [4] 4A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University , Moscow, Russia
                Author notes

                Edited by: Yun Liu, Fudan University, China

                Reviewed by: Marco Magistri, University of Miami, United States; Rowan Hardy, University of Birmingham, United Kingdom

                *Correspondence: Marina V. Nemtsova, nemtsova_m_v@ 123456mail.ru
                Andrey A. Zamyatnin Jr., zamyat@ 123456belozersky.msu.ru

                This article was submitted to Epigenomics and Epigenetics, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2019.00570
                6587113
                31258550
                c8147f18-e1df-4038-b464-1adaf904c823
                Copyright © 2019 Nemtsova, Zaletaev, Bure, Mikhaylenko, Kuznetsova, Alekseeva, Beloukhova, Deviatkin, Lukashev and Zamyatnin.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 March 2019
                : 31 May 2019
                Page count
                Figures: 0, Tables: 1, Equations: 0, References: 111, Pages: 13, Words: 0
                Categories
                Genetics
                Review

                Genetics
                rheumatoid arthritis,epigenetics,dna methylation,mirna,histone modifications,circrna
                Genetics
                rheumatoid arthritis, epigenetics, dna methylation, mirna, histone modifications, circrna

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