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.

Precision DNA demethylation ameliorates disease in lupus-prone mice

“…DNA methylation regulates gene expression and takes place at the cytosine residues in cytosine-guanine dinucleotides located most often between 1,000 bp and 800 bp upstream of the transcription start site. Conversion of cytosine to 5-methylcytosines is vital in many cellular processes, such as chromatin structure, transcription, and embryonic development (5,43). Aberrant DNA demethylation occurs actively in T cells from SLE patients (5,14), and growing evidence indicates that these DNA methylation changes closely correlate with disease activity (13,44).…”

Epigenetics in SLE

“…Historically, two classes of DNMTs were distinguished: (i) maintenance DNMTs (DNMT1) were believed solely responsible for re-methylation during cell division, while (ii) de novo DNMTs (DNMT3a and 3b) were claimed to confer DNA methylation independent of pre-existing patterns [ 2 – 4 ]. More recently, it has become increasingly clear that the historic classification was an over-simplification and that maintenance DNMTs can also confer de novo DNA methylation [ 3 ]. Indeed, DNA methylation and its regulation are more complex than previously assumed.…”

“…Methylated-CpG-binding proteins are structural proteins that recruit histone deacetylases (HDACs) and other chromatin remodeling factors. MBD proteins thereby aid in translating DNA methylation into histone modifications (see below) [ 3 ].…”

“…Altered methylation of genomic DNA in lymphocytes from SLE patients was linked to uncontrolled activation of mitogen activated protein kinases (MAPK). Impaired activation of protein kinase C (PKC)δ results in reduced activation of extracellular signal-regulated kinases (ERK) and impaired DNMT1 activity, subsequently contributing to reduced DNA methylation and increased expression of the costimulatory molecules CD11A, CD70, CD40L, the pro-inflammatory effector cytokine IL-17A, and several interferon-regulated genes [ 3 , 4 , 70 •, 71 ]. Another mechanism contributing to reduced DNMT1 expression is the increased expression of protein phosphatase 2A (PP2A), which suppresses ERK signaling and DNMT1 activity [ 49 , 50 ].…”

Multi‐omics integrative analysis identified SNP‐methylation‐mRNA: Interaction in peripheral blood mononuclear cells

“…7 Recently, disrupted DNA methylation patterns were established as a contributor to metabolic syndrome, 8,9 schizophrenia 10,11 and inflammatory or autoimmune disorders. 12,13 The feature and distribution of DNA methylation have been studied in a variety of tissues/cells, and these genome-wide maps of DNA methylation have revealed interesting features and provided important insights into its potential functions in genome regulation. 14,15 However, the functional mechanism underlying the variation in DNA methylation itself is still largely unknown.…”