Trends in Molecular Medicine
ReviewEpigenetic mechanisms in systemic lupus erythematosus and other autoimmune diseases
Section snippets
The concept of epigenetics and its involvement in autoimmune diseases
Despite the multitude of approaches utilized for determining the origin of autoimmune diseases, a definitive understanding of the pathogenic mechanisms involved remains poorly defined. Although Mendelian inheritance has been demonstrated for rare disorders, most autoimmune diseases are associated with polymorphisms in susceptibility genes and transmission rates are significantly lower than expected [1]. In these cases, environmental factors appear to influence disease onset, progression and
DNA methylation
Transcription factors need to bind to corresponding cis-DNA sequences to regulate gene transcription. Thus, transcription factors require an accessible DNA structure, and the most efficient way of gene silencing is to prevent transcription factor binding to DNA. One way to prevent binding is the addition of methyl groups by DNA methyltransferases (DNMTs) to the 5′ carbon position of cytosine within cytosine-phosphate-guanosine (CpG)-dinucleotides (Figure 1a) 3, 4. DNMT1 is responsible for
Histone modifications
A nucleosome is the basic subunit of chromatin and comprises 146 base pairs of DNA coiled around a histone octamer. The histone octamer consists of two copies each of the histone proteins H2A, H2B, H3 and H4. Histone complexes possess flexible N terminal tails that are accessible to post-translational modifications and strongly impact the functional capacities of nucleosomes [4]. Modifications include histone acetylation, methylation, ubiquitination, phosphorylation, sumoylation, deimination
Epigenetic modifications enhance immunogenicity and autoantibody production
The aforementioned components of the nucleosome are a major antigen source in SLE and other autoimmune diseases. Years prior to the development of clinical symptoms, SLE patients exhibit antinuclear antibodies and antibodies against extractable nuclear antigens [48]. Nucleosomes and histones as well as both single- and double-stranded DNA are detected in the serum of SLE patients and lupus-prone mice [49]. The presence of these intracellular components in the circulation has been explained by
miRNAs
miRNAs are 21 to 23 base pair RNAs and function as post-transcriptional and post-translational regulators of gene expression. miRNAs are transcribed from genomic, intergenic DNA by RNA polymerase II or III as preliminary transcripts (pri-miRNAs) (Figure 3) that are then cleaved by the nuclear ribonuclease Drosha 55, 56, 57 and exported to the cytoplasm. The cytoplasmic enzyme Dicer further processes the transcripts into mature miRNAs 58, 59. One or both strands form complexes with
Concluding remarks
A growing body of evidence implicating the involvement of epigenetic mechanisms in immune programming and the development of autoimmune diseases has accumulated over recent years. Reduced DNA methylation, histone hypoacetylation and hyperacetylation, and the overexpression of certain miRNAs, resulting in immune imbalance, have been shown to be associated with the onset and progression of autoimmune diseases (Table 1). Nevertheless, recent studies provide only the basis for understanding the
Conflict of interest statement
The authors have no conflicts of interest.
Acknowledgments
The authors thank Christine Hendrix for help with the preparation of the manuscript. Work performed in the authors’ lab was supported by grants from the National Institute of Allergy and Infectious Diseases and the National Institutes of Health.
Glossary
- cis-DNA sequences
- are elements that regulate gene expression within the same molecule (usually chromosomes). cis elements summarize CpG DNA, promoter and enhancer regions, locus control regions and matrix attachment sites. In contrast to cis regulatory elements, trans elements can regulate the expression of distant genes. Examples for trans regulatory elements are transcription factors, RNA polymerases, chromatin remodeling complexes and histone modifying enzymes (such as deacetylases,
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