DNA methylation in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease facilitated by aberrant immune responses directed against cells and tissues, resulting in inflammation and organ damage. In the majority of patients, genetic predisposition is accompanied by additional factors conferring disease expression. While the exact molecular mechanisms remain elusive, epigenetic alterations in immune cells have been demonstrated to play a key role in disease pathogenesis through the dysregulation of gene expression. Since epigenetic marks are dynamic, allowing cells and tissues to differentiate and adjust, they can be influenced by environmental factors and also be targeted in therapeutic interventions. Here, we summarize reports on DNA methylation patterns in SLE, underlying molecular defects and their effect on immune cell function. We discuss the potential of DNA methylation as biomarker or therapeutic target in SLE.

Keywords: CREM; DNMT; SLE; biomarker; chromatin; epigenetics; inflammation; methylation; transcription factor; treatment.

Figure 1.. Modifications to cytosine during DNA methylation.

Addition of a methyl group to the 5′ carbon position of cytosine within cytosine-phosphate-guanosine dinucleotides is a highly efficient mechanism for preventing transcription factor recruitment. DNA methylation is mediated through highly conserved enzymes, so-called DNA methyltransferases. DNA hydroxymethylation is the result of oxidation of methylated cytosine-phosphate-guanosine DNA by ten eleven translocation family enzymes, which makes it an intermediate product during active DNA demethylation processes. Hydroxymethylated cytosine may actively be removed by DNA repair pathways, suggesting a role of DNA hydroxymethylation during active DNA demethylation processes.

Figure 2.. Selected molecular mechanisms contributing to altered DNA methylation in systemic lupus erythematosus.

Cyclic adenosine-monophosphate response element modulator (CREM) α is expressed at increased levels in T cells from systemic lupus erythematosus (SLE) patients. Estrogen receptor signaling, increased CaMK4 activity, CD3/TCR stimulation, increased cellular calcium influx and also reduced DNA methylation of the CREM promoter P1 increase CREM-α expression. CREM-α contributes to regionally increased DNA methylation in SLE T cells through its interactions with DNMT1, and DNMT3a. Conversely, CREM-α reduces DNA methylation of the IL17 gene in a yet to be determined manner. Another DNA demethylation mechanism involves TET proteins in T cells from SLE patients. TET proteins mediate DNA hydroxymethylation (-OH), an intermediate of several active demethylation pathways. Growth arrest and DNA damage-inducible protein alpha (GADD45-α) is overexpressed in SLE T cells and further inducible by UV irradiation. GADD45α in conjunction with activation-induced deaminase, and methyl–cytosine-phosphate-guanosine-binding domain 4 related G:T glycosylase mediates DNA demethylation. Mitogen activated protein kinas (extracellular signal-regulated kinase) activation through the protein kinase C (PKC)-δ can be inhibited by hydralazine, or PP2A (which is increased in T cells from SLE patients). Impaired extracellular signal-regulated kinase activation results in reduced activity of DNMT1. Furthermore, DNMT expression and activity can be altered by miRNAs (miR-126, -129, -143) which are expressed at increased levels in SLE T cells. Examples of affected genes are provided below the depiction of DNA methylation patterns observed in SLE. The above-mentioned molecular mechanisms contributing to altered DNA methylation, however, have not been shown for all genes affected by DNA dysmethylation (also see Tables 1 & 2). AID: Activation-induced deaminase; CREM-α: Cyclic adenosine-monophosphate response element modulator alpha; DNMT: DNA methyltransferase; ERK: Extracellular signal-regulated kinase; MBD4: Methyl-CpG-binding domain 4; TET: Ten eleven translocation.