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SPECIAL FOCUS: 10-year anniversary issue - Review

Autoimmune disease in the epigenetic era: how has epigenetics changed our understanding of disease and how can we expect the field to evolve?

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Abstract

Autoimmune diseases are complex and enigmatic, and have presented particular challenges to researchers seeking to define their etiology and explain progression. Previous studies have implicated epigenetic influences in the development of autoimmunity. Epigenetics describes changes in gene expression related to environmental influences without alterations in the underlying genomic sequence, generally classified into three main groups: cytosine genomic DNA methylation, modification of various sidechain positions of histone proteins and noncoding RNAs feedback. The purpose of this article is to review the most relevant literature describing alterations of epigenetic marks in the development and progression of four common autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and Sjögren’s syndrome. The contribution of DNA methylation, histone modification and noncoding RNA for each of these disorders is discussed, including examples both of candidate gene studies and larger epigenomics surveys, and in various tissue types important for the pathogenesis of each. The future of the field is speculated briefly, as is the possibility of therapeutic interventions targeting the epigenome.

Financial & competing interests disclosure

This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01AI097134. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues
  • Studies describing epigenetic modifications (changes in DNA and chromatin protein secondary structure and noncoding RNA feedback affecting expression of gene products without alterations in the underlying DNA sequence) are becoming commonplace in the autoimmunity literature, but must be scrutinized carefully, as the interplay between epigenetic and genetic variation as it relates to disease phenotype is complex and not completely understood.

  • The overwhelming majority of studies performed so far in the field of autoimmune epigenetics have been case–control designs, and most have described differential DNA methylation in an epigenome-wide association study manner.

  • Systemic lupus erythematosus (SLE) is characterized by a global hypomethylation phenotype accompanied by a reduction in the maintenance DNA methyltransferase (DNMT)1, particularly in CD4+ T cells, where most epigenetic research has been focused.

  • A variety of hypomethylated genes appear to be key to SLE pathogenesis and have been described in several studies, including CD11a, CD70, perforin and CD40L in CD4+ T cells.

  • In SLE-naïve CD4+ T cells, a permissive epigenetic alteration in IFN-regulated genes is present before active gene expression, and explains the hypersensitivity of lupus peripheral blood mononuclear cells to type I IFN.

  • Genetic/epigenetic interactions have highlighted the complexity of SLE, particularly as it relates to MECP2/IRAK1 associations.

  • Rheumatoid arthritis (RA) patients’ T cells also exhibit a hypomethylated phenotype and a reduction in DNMT1, with strong evidence for genetic/epigenetic interaction in the MHC complex. By contrast, fibroblast-like synoviocytes present a hypermethylated phenotype.

  • Systemic sclerosis (SSc) is characterized by hypomethylation within CD4+ T-cell genes, including CD40L, like SLE.

  • In SSc, hypomethylation of collagen genes appears to play a key role in the fibrotic phenotype of this disease.

  • Sjögren’s syndrome has been less well studied than other autoimmune diseases; in naïve T cells, a hypomethylated phenotype is seen and several type I IFN genes are particularly differentially methylated.

  • Histone modifications have been less well studied in all autoimmune diseases than DNA methylation patterns.

  • In lupus, generalized hypoacetylation of H3 and H4 have been observed in mouse models, and reversing this with histone deacetylase inhibitors reduces disease. Human studies have shown significant increases in H4 acetylation in SLE monocytes; furthermore, patients and mouse models have antibodies that react more strongly to hyperacetylated H4 than ‘normally’ acetylated protein.

  • In RA, histone deacetylase 1 expression is dysregulated, and targeting of histone deacetylases does have therapeutic benefit in animal models.

  • SSc fibroblasts have a histone pattern similar to SLE; both H3 and H4 hypoacetylation is seen. Treatment of animal models with histone deacetylase inhibitors improves some aspects of disease.

  • miRNA studies are in their infancy in each of these autoimmune diseases. In lupus, large miRNA screens have been performed. Both miR-148a and miR-21 seem to have dual epigenetic effects, as they reduce the expression or function of DNMT machinery. A miRNA ‘signature’ consisting of 29 downregulated miRNAs has been described in SLE. Similarly, miR-363, miR-498 and miR-146a are differentially expressed in RA CD4+ T cells. miR-21 is also implicated in SSc.

  • No large histone or miRNA studies have been conducted in Sjögren’s syndrome.

  • In the next 5 years, we look forward to further epigenotyping of other, perhaps less obvious cell types in these diseases, guided by our growing databases of genetic and epigenetic disease associations. We anticipate the development of biomarker assays for several of these diseases based upon epigenetic alterations, and perhaps the utilization of epigenetically active therapeutics to complement traditional drugs.

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