Epigenetics in Rheumatoid Arthritis

Abstract

PURPOSE OF REVIEW To give an overview of recently published articles addressing the role of epigenetic modifications in rheumatoid arthritis (RA). Here we focused on DNA methylation and posttranslational histone modifications. RECENT FINDINGS Recent studies attempted to link epigenetic modifications with genetic or environmental risk factors for RA. There is evidence that histone deacetylases confer effects of environmental triggers such as smoking, diet or therapy on expression levels of target genes. Additionally, disturbed methylation patterns and cell-type specific histone methylation marks were identified as potential mediators of genetic risk in RA. Altered methylome signatures were found in several cell types in RA, first of all RA synovial fibroblasts, and contribute to the intrinsic fibroblast activation. The reversal of DNA hypomethylation by inhibiting the polyamine recycling pathway was suggested as new epigenetic therapy in RA. Moreover, targeting epigenetic reader proteins, such as bromodomain proteins, emerged as a new field in drug development and the first studies underscored the potential of these drugs not only in malignant and inflammatory conditions but also in autoimmune diseases. SUMMARY Epigenetic factors represent a promising area to link genetics, regulation of gene expression and environmental risk factors. C URRENT OPINION Epigenetics in rheumatoid arthritis Kerstin Klein and Steffen GayPurpose of review To give an overview of recently published articles addressing the role of epigenetic modifications in rheumatoid arthritis (RA). Here we focused on DNA methylation and posttranslational histone modifications. Recent findingsRecent studies attempted to link epigenetic modifications with genetic or environmental risk factors for RA. There is evidence that histone deacetylases confer effects of environmental triggers such as smoking, diet or therapy on expression levels of target genes. Additionally, disturbed methylation patterns and cell-type specific histone methylation marks were identified as potential mediators of genetic risk in RA. Altered methylome signatures were found in several cell types in RA, first of all RA synovial fibroblasts, and contribute to the intrinsic fibroblast activation. The reversal of DNA hypomethylation by inhibiting the polyamine recycling pathway was suggested as new epigenetic therapy in RA. Moreover, targeting epigenetic reader proteins, such as bromodomain proteins, emerged as a new field in drug development and the first studies underscored the potential of these drugs not only in malignant and inflammatory conditions but also in autoimmune diseases. SummaryEpigenetic factors represent a promising area to link genetics, regulation of gene expression and environmental risk factors.

TLR2 Promoter Hypermethylation Creates Innate Immune Dysbiosis

“…These epigenetic changes either at the level of DNA or histone can modify the cellular phenotype. For example, substantial work has been done with respect to epigenetics in cancer biology, epigenetic alterations with inflammation including age-related and airway inflammation, bronchial asthma, and autoimmune diseases such as lupus erythematosus and rheumatoid arthritis (Esteller 2008;Trenkmann et al 2010).…”

Alterations in type I hemidesmosome components suggestive of epigenetic control in the salivary glands of patients with Sjögren's syndrome

“…The development of autoimmune diseases has recently been linked to alterations in epigenetic silencing patterns (13,14). Indeed, we detected BP230 gene hypermethylation in the LSGs of patients with SS (P ϭ 0.018), which suggests that BP230 mRNA levels are controlled by epigenetic mechanisms.…”

“…In synovial fibroblasts from the joints of RA patients, hypermethylation in promoters of proapoptotic genes was observed. These observations may be related to increased cell survival (14,34,35). Alterations in the expression of apoptosis-related genes, observed using cDNA microarrays for epithelial cells of LSGs from patients with SS (36), might also reflect differential methylation or additional epigenetic mechanisms (37).…”

“…Interestingly, autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis, have been linked to alterations in epigenetic control (12,13). Altered hypomethylation patterns in the DNA of T and B lymphocytes are associated with the pathogenesis of SLE and RA (12,14). The promoter of the death receptor 3 (DR-3) gene in synovial fibroblasts from RA patients contains one CpG island that is hypermethylated and causes downregulation of DR-3 (15).…”

Epigenética e doenças humanas

“…Alterações epigenéticas também têm sido relacionadas com doenças autoimunes, como a hipometilação encontrada em doenças como lúpus eritematoso, artrite reumatóide, escleroderma e doenças de pele inflamatórias (MILLINGTON, 2008;BROOKS et al, 2010;TRENKMANN et al, 2010). Na diabetes tipo I, há uma diminuição de expressão do gene HDAC e aumento da dimetilação em H3K4 em linfócitos, o que pode estar relacionado com a resposta imune alterada dessas células ao destruírem as células β produtoras de insulina no pâncreas (COOPER; EL-OSTA, 2010).…”