Epigenetic modifications in rheumatoid arthritis

Abstract

Over the last decades, genetic factors for rheumatoid diseases like the HLA haplotypes have been studied extensively. However, during the past years of research, it has become more and more evident that the influence of epigenetic processes on the development of rheumatic diseases is probably as strong as the genetic background of a patient. Epigenetic processes are heritable changes in gene expression without alteration of the nucleotide sequence. Such modifications include chromatin methylation and post-translational modification of histones or other chromatin-associated proteins. The latter comprise the addition of methyl, acetyl, and phosphoryl groups or even larger moieties such as binding of ubiquitin or small ubiquitin-like modifier. The combinatory nature of these processes forms a complex network of epigenetic modifications that regulate gene expression through activation or silencing of genes. This review provides insight into the role of epigenetic alterations in the pathogenesis of rheumatoid arthritis and points out how a better understanding of such mechanisms may lead to novel therapeutic strategies.

Figure 1

Close interactions between DNA methylation and histone modifications. (a) Relaxed chromatin is accessible for transcription factors (TFs). Chemical modifications (green) on the core histones (yellow) result in a relaxed chromatin structure. (b) DNA methyltransferases (Dnmts) add methyl groups (grey triangle) to CpG dinucleotides, resulting in gene silencing that can affect the former modification of the histones. (c) The chemical modification (red) to the core histone results in a condensed and inactive chromatin structure. TFs are sterically hindered and cannot bind to their recognition sequence on the DNA.

Figure 2

MicroRNA (miRNA) biogenesis. The canonical pathway includes cleavage of pri-miRNAs in the nucleus by Drosha, whereas pre-miRNAs are processed by Dicer in the cytoplasm. Some of the miRNAs located within introns of protein-coding genes bypass Drosha cleavage. These so-called mirtrons are processed from their primary transcripts within an alternative (mirtronic) pathway by splicing and debranching. Finally, from the resulting miRNA duplex, the strand with the higher affinity is assembled into the RNA-induced silencing complex. Complementary base pairing with the target mRNA leads either to degradation of the mRNA or to translational repression, depending on the complement of the sequences. This figure has been modified according to [40]. Ago, Agonaute proteins.