An update on the role of epigenetics in systemic vasculitis

Abstract

Purpose of review: The purpose of this review is to discuss recent observations of epigenetic changes related to the complex pathogenesis of systemic vasculitides and their contribution to the field.

Recent findings: There have been new observations of epigenetic changes in vasculitis and their potential role in disease pathogenesis in antineutrophil cytoplasmic antibody-associated vasculitis, giant-cell arteritis, Kawasaki disease, Behçet's disease, and IgA vasculitis. Some of this recent work has focused on the efficacy of using DNA methylation and miRNA expression as clinical biomarkers for disease activity and how DNA methylation and histone modifications interact to regulate disease-related gene expression.

Summary: DNA methylation, histone modification, and miRNA expression changes are all fruitful ground for biomarker discovery and therapeutic targets in vasculitis. Current knowledge has provided targeted and suggested effects, but in many cases, has relied upon small cohorts, cosmopolitan cell populations, and limited knowledge of functional interactions. Expanding our knowledge of how these epigenetic mechanisms interact in a disease-specific and cell-specific manner will help to better understand the pathogenesis of systemic vasculitis.

FIGURE 1

A cartoon model of epigenetic control of MPO and PRTN3 in ANCA-associated vasculitis. Ciavatta et al. and Yang et al. suggest that histone modifications surrounding the promoter and enhancer regions of MPO and PRTN3 in AAV are in a bivalent state (presence of both repressive and permissive marks), maintaining gene silencing in mature neutrophils that is disrupted in AAV patients. In neutrophils from healthy controls and inactive patients with low MPO and PR3 expression, JMJD3 demethylates H3K27, although PRC2 remethylates it in kind to maintain a condensed silent state. EHMT1 and EHMT2 assist by maintaining H3K9me2 in the same region. Permissive H3K4me2 marks suggest an epigenetic poising and are present in both patients and controls, though the MLL2, MLL3, and MLL4 genes that regulate this mark were overexpressed in patients compared with controls. DNA methylation of the gene promoter and enhancer regions provides a second method of epigenetic control, preventing the access of transcriptional machinery, and CpG islands can be targeted by PRC2 as well for H3K27me3. In patients with active disease, some disruptive process interrupts the gene silencing and a decrease in RUNX3 expression prevents the reestablishment of H3K27me3. Decreased expression of EHMT1 and EHMT2 correlates with depletion of H3K9me2 and an increase in MSL1 expression correlates with enriched H4K16ac, a mark of gene activation. Jones et al. found that leukocytes from active AAV patients have decreased DNMT1 expression and a site-specific decrease in DNA methylation, suggesting a process that targets specific loci including MPO and PRTN3 and allows for gene expression. When AAV is inactive, methylation at these loci is returned to levels near that of healthy controls and expression is reduced. This suggests that MPO and PRTN3 DNA methylation is a disease-specific process supported by the identification of a CpG site in the PRTN3 promoter (CpG #13) that is demethylated in patients with a higher risk of relapse. AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; MPO, myeloperoxidase; proteinase 3; PR3, proteinase 3.