Overexpression of transcripts containing LINE-1 in the synovia of patients with rheumatoid arthritis

Ali, Manir; Veale, Douglas J.; Reece, R. J.; Quinn, Mark; Henshaw, K; Zanders, Edward D.; Markham, Alex F.; Emery, Paul; Isaacs, John D.

doi:10.1136/ard.62.7.663

Cited by 26 publications

(15 citation statements)

References 9 publications

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“…Moreover, repetitive sequences such as L1, Alu, and satellite alpha repeats are silenced by methylation in normal cells and can be used as markers of global hypomethylation (11). Our group and others (12, 13) reported a reactivation of the endogenous retroviral element L1 in the RA synovial lining and at sites of invasion. These reports suggest that global genomic hypomethylation plays a role in the pathogenesis of RA, and that genes normally silenced by methylation might contribute to the activated phenotype of RASFs (12).…”

mentioning

confidence: 58%

DNA hypomethylation in rheumatoid arthritis synovial fibroblasts

Karouzakis

Michel

Neidhart

2009

Arthritis & Rheumatism

276

222

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Objective. Rheumatoid arthritis synovial fibroblasts (RASFs) are phenotypically activated and aggressive. We undertook this study to investigate whether the intrinsic activation of RASFs is due to global genomic hypomethylation, an epigenetic modification.Methods. Global genomic hypomethylation was assessed by immunohistochemistry, flow cytometry, and L1 promoter bisulfite sequencing. The levels of Dnmt1 were determined in synovial tissue and cultured SFs by Western blotting before and after treatment with cytokines and growth factors. Normal SFs were treated for 3 months with a nontoxic dose of the DNA hypomethylation drug 5-azacytidine (5-azaC), and changes in gene expression were revealed using complementary DNA arrays. The phenotypic changes were confirmed by flow cytometry.Results. In situ and in vitro, RASF DNA had fewer 5-methylcytosine and methylated CG sites upstream of an L1 open-reading frame than did DNA of osteoarthritis SFs, and proliferating RASFs were deficient in Dnmt1. Using 5-azaC, we reproduced the activated phenotype of RASFs in normal SFs. One hundred eighty-six genes were up-regulated >2-fold by hypomethylation, with enhanced protein expression. These included growth factors and receptors, extracellular matrix proteins, adhesion molecules, and matrix-degrading enzymes. The hypomethylating milieu induced irreversible phenotypic changes in normal SFs, which resembled those of the activated phenotype of RASFs.

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confidence: 58%

DNA hypomethylation in rheumatoid arthritis synovial fibroblasts

Karouzakis

Michel

Neidhart

2009

Arthritis & Rheumatism

276

222

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“…It is also possible that the expression of certain transcription factors was increased by DNA demethylation, which then started to activate downstream pathways. Strong in vivo evidence for a functional effect of DNA hypomethylation in RA synovium is the aberrant expression of LINE-1 (long interspersed nucleotide elements-1) retrotransposons in RA patients [62,63]. LINE-1 retrotransposons are mobile genetic elements, which constitute around 17% of mammalian genomes and are typically silenced by DNA methylation.…”

Section: Epigenetic Changes In the Ra Synoviummentioning

confidence: 99%

Epigenetics Changes in the RA Synovium

Ospelt

2012

CRR

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The fast technological progress of bio-medical research in the last decade led to the accumulation of vast amounts of data and opened new fields of research, such as epigenetics. Nevertheless, the pathogenesis of most complex diseases is still not understood. The current review discusses pathological changes in the adaptive immune system as well as in the synovium of rheumatoid arthritis (RA) patients. The main focus lies on epigenetic changes found in RA synovial cells, which might help to understand not only how environmental factors can influence disease development, but mainly why inflammation in RA joints is not resolved and why constant activation of the immune system and progressive joint destruction prevail.

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“…A complete database of HERVs can be found online (). It should also be noted that mobile genetic elements that behave as HERVs, such as LINE-1, have been implicated in RA [14]. LINE-1 is a DNA sequence that can change its relative position within the genome of a single cell, leading to phenotypically significant mutations.…”

Section: Hervs: Origin and Classificationmentioning

confidence: 99%

Human Endogenous Retroviruses (HERVs) and Autoimmune Rheumatic Disease: Is There a Link?

Tugnet¹,

Rylance²,

Roden³

et al. 2013

TORJ

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Autoimmune rheumatic diseases, such as RA and SLE, are caused by genetic, hormonal and environmental factors. Human Endogenous Retroviruses (HERVs) may be triggers of autoimmune rheumatic disease. HERVs are fossil viruses that began to be integrated into the human genome some 30-40 million years ago and now make up 8% of the genome. Evidence suggests HERVs may cause RA and SLE, among other rheumatic diseases. The key mechanisms by which HERVS are postulated to cause disease include molecular mimicry and immune dysregulation. Identification of HERVs in RA and SLE could lead to novel treatments for these chronic conditions. This review summarises the evidence for HERVs as contributors to autoimmune rheumatic disease and the clinical implications and mechanisms of pathogenesis are discussed.

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Overexpression of transcripts containing LINE-1 in the synovia of patients with rheumatoid arthritis

Cited by 26 publications

References 9 publications

DNA hypomethylation in rheumatoid arthritis synovial fibroblasts

DNA hypomethylation in rheumatoid arthritis synovial fibroblasts

Epigenetics Changes in the RA Synovium

Human Endogenous Retroviruses (HERVs) and Autoimmune Rheumatic Disease: Is There a Link?

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