Translating epigenetics into clinic: focus on lupus

Abstract

Systemic lupus erythematosus (SLE) is a chronic relapsing-remitting autoimmune disease with highly heterogeneous phenotypes. Biomarkers with high sensitivity and specificity are useful for early diagnosis as well as monitoring disease activity and long-term complications. Epigenetics potentially provide novel biomarkers in autoimmune diseases. These may include DNA methylation changes in relevant lupus-prone genes or histone modifications and microRNAs to upregulate and downregulate relevant gene expression. The timing and nature of epigenetic modification provide such changes. In lupus, DNA methylation alterations in cytokine genes, such as IFN-related gene and retrovirus gene, have been found to offer biomarkers for lupus diagnosis. Histone modifications such as histone methylation and acetylation lead to transcriptional alterations of several genes such as PTPN22, LRP1B, and TNFSF70. There are varieties of microRNAs applied as lupus biomarkers, including DNMT1-related microRNAs, renal function-associated microRNAs, microRNAs involved in the immune system, and microRNAs for phenotype classification. Thus, we conclude a wide range of promising roles of epigenetic biomarkers aiding in the diagnosing and monitoring of lupus diseases and the risk of organ damage.

Keywords: Biomarker; DNA methylation; Epigenetic modification; Histone modification; MicroRNAs; Systemic lupus erythematosus.

Fig. 1

A description of the three main epigenetic mechanisms involved in SLE pathogenesis: DNA methylation, histone modification, and RNA-based mechanisms, which can alter genome and generate various gene expression profiles. DNA methylation is catalyzed by transferring a methyl group to the five positions of cytosine in DNA. Histone modifications refer to covalent posttranslational modifications of the nucleosomal histones H2A, H2B, H3, and H4, with one H3–H4 tetramer and two H2A–H2B dimers. The lysine and arginine residues of histone proteins that extrude from the nucleosome can be modified via methylation, acetylation, phosphorylation, or ubiquitylation, which can be altered with variants or chemical modifications on their histone tails. The most recent mechanism of epigenetic inheritance involves some RNAs, which may play a significant role in producing higher-order chromatin structures in nucleosomal chains. Several methylation-sensitive genes (CD11a, CD70, perforin, CD40L IFN-related genes, and CD5), histone modifications (histone deacetylation, H3k4me2, and H3K4me3), and microRNAs (miR-21, miR-126, miR-148a, miR-125a, miR-142, miR-29, miR-101, miR-17–miR-92) have been noted to illustrate their involvement in lupus pathogenesis