DNA methylome signature in rheumatoid arthritis

1Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, USA.
Annals of the rheumatic diseases (Impact Factor: 10.38). 06/2012; 72(1). DOI: 10.1136/annrheumdis-2012-201526
Source: PubMed


Epigenetics can influence disease susceptibility and severity. While DNA methylation of individual genes has been explored in autoimmunity, no unbiased systematic analyses have been reported. Therefore, a genome-wide evaluation of DNA methylation loci in fibroblast-like synoviocytes (FLS) isolated from the site of disease in rheumatoid arthritis (RA) was performed.

Genomic DNA was isolated from six RA and five osteoarthritis (OA) FLS lines and evaluated using the Illumina HumanMethylation450 chip. Cluster analysis of data was performed and corrected using Benjamini-Hochberg adjustment for multiple comparisons. Methylation was confirmed by pyrosequencing and gene expression was determined by qPCR. Pathway analysis was performed using the Kyoto Encyclopedia of Genes and Genomes.

RA and control FLS segregated based on DNA methylation, with 1859 differentially methylated loci. Hypomethylated loci were identified in key genes relevant to RA, such as CHI3L1, CASP1, STAT3, MAP3K5, MEFV and WISP3. Hypermethylation was also observed, including TGFBR2 and FOXO1. Hypomethylation of individual genes was associated with increased gene expression. Grouped analysis identified 207 hypermethylated or hypomethylated genes with multiple differentially methylated loci, including COL1A1, MEFV and TNF. Hypomethylation was increased in multiple pathways related to cell migration, including focal adhesion, cell adhesion, transendothelial migration and extracellular matrix interactions. Confirmatory studies with OA and normal FLS also demonstrated segregation of RA from control FLS based on methylation pattern.

Differentially methylated genes could alter FLS gene expression and contribute to the pathogenesis of RA. DNA methylation of critical genes suggests that RA FLS are imprinted and implicate epigenetic contributions to inflammatory arthritis.

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Available from: John William Whitaker, Oct 04, 2015
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    • "Autoimmune-related epigenetic dysregulations, in particular DNA methylation, have already been described in systemic lupus erythematosus (SLE), rheumatoid arthritis and systemic sclerosis patients (Jeffries et al., 2011; Nakano et al., 2013; Lian et al., 2012). Moreover, the higher incidence of autoimmune diseases in women can be partly explained by X chromosome inactivation, a major epigenetics-controlled event (Chitnis et al., 2000; Hewagama et al., 2006; Richardson et al., 1990). "
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    ABSTRACT: Increasing evidence supports the role of epigenetics in the development of autoimmune disorders and the possibility of using epigenetic modifying drugs in the context of MS has not yet been investigated. We have explored the effect of the hypomethylating agent 5-aza-2′-deoxycytidine (DAC) in two murine models of experimental allergic encephalomyelitis (EAE). DAC treatment was associated with a significant amelioration of the clinical and histological hallmarks of EAE in both models. These effects were observed both in prophylactic and therapeutic regimens. The milder course of the disease was associated with a reduction in the number of spinal cord infiltrating lymphocytes and amelioration of the histopathological signs associated with EAE. In addition, increased transcript levels of anti-inflammatory cytokines and decreased mRNA expression of pro-inflammatory mediators were also observed. Finally, DAC treatment increased the percentage of circulating regulatory T cells by inducing Foxp3 expression via demethylation of a CpG island in Foxp3. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 12/2014; 229(12). DOI:10.1002/jcp.24641 · 3.84 Impact Factor
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    • "The expression of inflammatory cytokines can be modulated by changes in the methylation status of promoter regions (Fu et al., 2011). The expression of TNF increases in macrophages following exposure to LPS, but differences in the methylation state of the TNF promoter are involved in driving the various levels of TNF gene expression, thus explaining the variations in responses in individual with chronic inflammatory diseases (Wilson, 2008; Nakano et al., 2013; Nimmo et al., 2012). Similarly, the IL-1␤ promoter in promyeloid cells is demethylated during differentiation into monocytic cells, thus facilitating accessibility to the promoter and allowing the subsequent production of IL-1␤ (Wessels et al., 2010). "
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    The International Journal of Biochemistry & Cell Biology 08/2014; 55. DOI:10.1016/j.biocel.2014.08.005 · 4.05 Impact Factor
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    • "Classical approaches were first tested to compute the differentially methylated (DM) loci. Although Student t-test [25] has been found to be applied to 450 K microarray data [26], data distribution (see Additional file 6) presents a clearly non-normal behaviour, limiting therefore the validity of the test. Similarly, while SAM [8] and LIMMA [9] do not require a rigorous normal distribution and -especially the latter- shows good performance when the sample size is small, we observed that they are not robust enough for cases showing dramatic deviation from normality, a fact also mentioned in LIMMA’s manual. "
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    BMC Medical Genomics 03/2014; 7(1):12. DOI:10.1186/1755-8794-7-12 · 2.87 Impact Factor
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