Epigenetic modifications in rheumatoid arthritis, a review
Graphical abstract
Highlights
► RA synovial fibroblasts display an aberrant DNA methylome signature. ► Histone deacetylase inhibitors have beneficial effects in RA. ► Histone deacetylase inhibitors have epigenetic and non-epigenetic effects.
Section snippets
What is epigenetics?
Originally, epigenetic mechanisms were considered as heritable changes in gene function that were not explainable by changes in the DNA sequence. A more revised definition of epigenetics is the structural adaption of chromosomal regions in order to register, signal or perpetuate altered activity states [3]. Epigenetic modifications including DNA methylation and covalent histone modifications such as acetylation, methylation and ubiquitination alter the accessibility of DNA to the transcription
DNA methylation
RASF display a DNA methylome signature that distinguishes them from osteoarthritis synovial fibroblasts (OASF) and normal SF [9, 10•]. Whereas Karouzakis et al. described a global hypomethylation in RASF compared to OASF [9], Nakano et al. investigated both hypomethylation and hypermethylation patterns in RASF [10•]. A global hypomethylation was also found in peripheral blood mononuclear cells (PBMCs) isolated from RA patients compared to healthy controls [11]. Hypomethylation was identified in
Histone methylation
Studies looking at histone methylation in the context of RA are scarce. The histone methyltransferase EZH2 was shown to be overexpressed in RASF compared to OASF [21•]. EZH2 generates the trimethyl mark on histone 3 lysine 27 (H3K27me3) which is associated with the transcriptional silencing of genes [7]. The tumor suppressor gene secreted frizzled-related protein 1 (SFRP1), an inhibitor of the wingless type MMTV integration site (Wnt) signaling pathway, was show to be a target of EZH2 activity
Histone acetylation
In the past eight years not only certain beneficial effects of HDAC inhibitors in therapeutic approaches but also preventive approaches in different animal models of RA have been reported [24, 25, 26, 27, 28]. Although some decrease in disease severity was shown, these studies have in common that the used inhibitors lack specificity for a single HDAC isoform and the underlying mechanisms remained obscure. In addition, there are some discrepancies in the literature not only about HDAC expression
Other histone modifications
So far, only one report exists investigating the functional interaction of sumoylation and epigenetic changes in RASF. RASF have intrinsically high levels of the small ubiquitin like modifier (SUMO)-1 paralleled by decreased levels of its specific protease SENP1. Transient overexpression of SENP1 in RASF reduced H4 acetylation in the MMP1 promoter and consequently MMP1 expression, leading to a decreased invasiveness. The authors further showed that the mechanism was dependent on the presence of
Conclusions
In recent years, altered DNA methylation patterns and histone modifications including acetylation, methylation and sumoylation emerged as contributors in the pathogenesis of RA. The field of epigenetics has great potential of finding completely new targets for the treatment of RA. So far, most results are based on in vitro data and only little information exists about in vivo mechanisms. Available in vivo studies are based on the usage of HDAC inhibitors, which have, as recent in vitro studies
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by a grant of IAR, and by the IMI funded project BeTheCure (115142-2).
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