Epigenetic mechanisms in systemic lupus erythematosus and other autoimmune diseases

Abstract

The pathogenic origin of autoimmune diseases can be traced to both genetic susceptibility and epigenetic modifications arising from exposure to the environment. Epigenetic modifications influence gene expression and alter cellular functions without modifying the genomic sequence. CpG-DNA methylation, histone tail modifications and microRNAs (miRNAs) are the main epigenetic mechanisms of gene regulation. Understanding the molecular mechanisms that are involved in the pathophysiology of autoimmune diseases is essential for the introduction of effective, target-directed and tolerated therapies. In this review, we summarize recent findings that signify the importance of epigenetic modifications in autoimmune disorders while focusing on systemic lupus erythematosus. We also discuss future directions in basic research, autoimmune diagnostics and applied therapy.

Figure 1

A) Structure of cytosine and 5-methyl-cytosine. DNA methyltransferases (DNMTs) methylate cytosine groups in CpG sequences. B) Schematic representation of DNA methylation patterns in a silenced region (upper panel), compared to a transcriptionally active region (lower panel). Open circles represent un-methylated, filled circles methylated CpGs. C) Methylated CpG (C^mpG) demethylation by GADD45a. DNA demethylation may occur through a two-step enzymatic process, promoted by GADD45a. The first step involves deamination of C^mpG nucleotides by activation-induced deaminase (AID), generating a thymine product and a G:T mismatch. The second step involves thymine base removal by methyl-CpG-binding domain 4 (MBD-4). In the following, the missing base gets replaced by a non-methylated cytosine group, resulting in demethylation of C^mpG dinucleotides [36].

Figure 2

A) Nucleosome arrangement in transcriptionally inactive heterochromatin and active euchromatin. Compact heterochromatin is characterized by dense nucleosome packing, repressive histone modifications and high degrees of DNA methylation (purple circles). Euchromatin is characterized by de-compaction of nucleosome fibers, permissive histone modifications and a low degree of DNA methylation. In accessible regions, transcription regulatory factors can bind to DNA motifs and induce transcription. In these regions, DNA is accessible to DNases (DNase hypersensitivity site). B) Schematic of the (hypothetical) model depicting the interplay between DNA methyltransferases (DNMTs) and histone methyltransferases (using the example of G9a). HP1 is an adapter complex that promotes the interplay between DNMTs and histone methyltransferases. Thereby, HP1 promotes DNA methylation by DNMTs. The association of DNMTs with G9a could, in turn, allow a direct impact of DNA methylation on H3K9 methylation states [44].

Figure 3. Schematic display of gene regulation by miRNAs

MicroRNAs (miRNAs) are derived from primary genomic DNA transcripts (pri-miRNAs). Pri-miRNAs are processed by the ribonuclease Drosha to pre-miRNAs. These are then transported to the cytoplasm and subsequently processed into mature 21 to 23 nucleotide miRNAs by Dicer. MiRNAs are incorporated into a RNP complex that exerts regulatory miRNA functions. MiRNA regulatory functions are transcript degradation and translational arrest.