Autoimmune disease: a view of epigenetics and therapeutic targeting

Abstract

Autoimmune diseases comprise a large group of conditions characterized by a complex pathogenesis and significant heterogeneity in their clinical manifestations. Advances in sequencing technology have revealed that in addition to genetic susceptibility, various epigenetic mechanisms including DNA methylation and histone modification play critical roles in disease development. The emerging field of epigenetics has provided new perspectives on the pathogenesis and development of autoimmune diseases. Aberrant epigenetic modifications can be used as biomarkers for disease diagnosis and prognosis. Exploration of human epigenetic profiles revealed that patients with autoimmune diseases exhibit markedly altered DNA methylation profiles compared with healthy individuals. Targeted cutting-edge epigenetic therapies are emerging. For example, DNA methylation inhibitors can rectify methylation dysregulation and relieve patients. Histone deacetylase inhibitors such as vorinostat can affect chromatin accessibility and further regulate gene expression, and have been used in treating hematological malignancies. Epigenetic therapies have opened new avenues for the precise treatment of autoimmune diseases and offer new opportunities for improved therapeutic outcomes. Our review can aid in comprehensively elucidation of the mechanisms of autoimmune diseases and development of new targeted therapies that ultimately benefit patients with these conditions.

Keywords: DNA methylation; RNA modification; autoimmune disease; epigenetic; histone modification; systemic lupus erythematosus.

Figure 1

An overview of epigenetic mechanisms. The basic unit of chromatin is the nucleosome. Two molecules of H2A, H2B, H3, and H4 form a histone octamer, and DNA molecules are coiled around the histone octamer to form the nucleosome’s core particles. DNA methylation is mediated by the enzyme DNA methyltransferase (DNMT), which transfers methyl groups to adenine (A), guanine (G), or cytosine (C) by using S-adenosyl methionine (SAM) as a substrate. Histone modifications include acetylation, methylation, phosphorylation and so on, and they mainly occur on lysine (K), arginine (R) and serine (S). RNA modifications are similar to DNA modifications, including m1A, m6A and many other types. Chemical structures are prepared using ChemDraw.

Figure 2

Epigenetic modification of immune cells in autoimmune diseases. Gene transcription in immune cells in autoimmune diseases is affected by epigenetic mechanisms such as histone modification and DNA methylation. In Treg cell from experimental autoimmune encephalomyelitis (EAE), DNMT inhibitor 5-Aza can promote Foxp3 transcription, and inhibit IL-17A transcription, thus ameliorating CNS inflammatory responses and decreasing proinflammatory cytokines. HDAC inhibitor can increase histone acetylation modification and promote IFN-γ transcription in T cell in T1D. (Figure created by Figdraw, ID: TUIUU9ee14).

Figure 3

A timeline for studying histone modifications. Phillips identifies histone lysine acetylation (111). Allfrey et al. identify histone acetylation as transcription regulators (112). Taunton et al. identify the first histone deacetyltransferase (113). Brownell et al. identify the first histone acetyltransferase (114). Dhalluin et al. identify bromodomain as the first histone acetylation reader (115). Rea et al. identify the first histone methyltransferase SUV39H1 (116). Bannister et al. identify chromodomain as the first histone methylation reader (117). Shi et al. identify the first histone demethylase LSD1 (118). Zhao et al. identify the histone crotonylation (119). Zhao et al. identify the histone lactylation (120).

Figure 4

The crossroads of epigenetics and immune pathways. Epigenetics plays an integral role in the regulation of immune pathways. In the TLR signaling pathway, histone methyltransferase SYMD5 catalyzes H4K20me3 to repress TLR4 expression; histone demethylase PHF2 activates TLR4 expression by removal of H3K9me1. Knockdown of JNK will inhibit m6A and METTL3 expression; In the sGAS-STING signaling pathway, DNA demethylases TET2 elevate cGAS levels, histone demethylases KDM5B and KDM5C inhibit STING expression. Histone demethylase Jmjd3 upregulates NF-kB-mediated inflammatory cytokine levels by removal of H3K27me3; In the JAK-STAT signaling pathway, activator of transcription STAT recruits histone acetyltransferases and chromatin-remodeling enzymes, and histone methyltransferase EZH2 and histone acetyltransferase p300 elevate STAT levels. IFN-γ produced by this signaling pathway can induce H3K27me3, which is associated with gene repression; In the PD-1 and PD-L1 pathway, knockdown of METTL3 abolishes m6A modification and reduces stabilization of PD-L1 mRNA, and m6A reader IGF2BP and YTHDF regulates RNA stability and expression levels of PD-L1. DNA methyltransferase inhibitor 5-aza-2’ deoxycytidine (decitabine) enhances PD-1 expression. PAMP, pathogen associated molecular pattern; DAMP, damage associated molecular pattern; TLR, Toll-like receptors; IRAK, interleukin-1 receptor-associated kinase; TRAF6, Tumor necrosis factor receptor-associated factor 6; IRF3, Interferon regulatory factor 3; ISGs, Interferon-stimulated genes.