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Review
. 2023 Oct 2;25(1):189.
doi: 10.1186/s13075-023-03149-w.

M6A methylation modification in autoimmune diseases, a promising treatment strategy based on epigenetics

Affiliations
Review

M6A methylation modification in autoimmune diseases, a promising treatment strategy based on epigenetics

Yurong Huang et al. Arthritis Res Ther. .

Abstract

Background: N6-methyladenosine (m6A) methylation modification is involved in the regulation of various biological processes, including inflammation, antitumor, and antiviral immunity. However, the role of m6A modification in the pathogenesis of autoimmune diseases has been rarely reported.

Methods: Based on a description of m6A modification and the corresponding research methods, this review systematically summarizes current insights into the mechanism of m6A methylation modification in autoimmune diseases, especially its contribution to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

Results: By regulating different biological processes, m6A methylation is involved in the pathogenesis of autoimmune diseases and provides a promising biomarker for the diagnosis and treatment of such diseases. Notably, m6A methylation modification is involved in regulating a variety of immune cells and mitochondrial energy metabolism. In addition, m6A methylation modification plays a role in the pathological processes of RA, and m6A methylation-related genes can be used as potential targets in RA therapy.

Conclusions: M6A methylation modification plays an important role in autoimmune pathological processes such as RA and SLE and represents a promising new target for clinical diagnosis and treatment, providing new ideas for the treatment of autoimmune diseases by targeting m6A modification-related pathways.

Keywords: Autoimmune diseases; Methylation regulation; Rheumatoid arthritis; Systemic lupus erythematosus; m6a methylation modification.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The roles of writers, erasers, and readers in the m6A modification of mRNA. The dynamic process of RNA adenine methylation is driven by three major groups of enzymes called writers, erasers, and readers, which are responsible, respectively, for methylation, demethylation, and decoding of the methylation code. The m6A methylation process is catalyzed by a writer complex, which includes METTL3, METTL14, METTL16, WTAP, VIRMA, RBM15/15B, CBLL1, KIAA1429, and ZC3H13. The m6A eraser demethylases include FTO and ALKBH5. The m6A readers are proteins that recognize and bind to m6A marks, affecting the fate and function of the modified RNAs. The known m6A readers are YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, and HNRNPC/A2B1
Fig. 2
Fig. 2
Molecular function of m6A in mRNA metabolism. Specific m6A-binding reading proteins regulate mRNA metabolism containing m6A, including m6A co-transcription modifications, m6A promoting alternative splicing, m6A promoting mRNA export, m6A altering RNA structure, m6A regulating translation efficiency, and m6A regulating mRNA stability. (The thick line represents the encoding sequence, and the thin line represents the UTR. The dashed box indicates the thermal shock state.)
Fig. 3
Fig. 3
Genes with abnormal m6A methylation are involved in the pathogenesis of RA. A IGFBP2 influences the interaction between FLS by regulating the neuropeptides GHR and NPR2. IGF2BP3 regulates G2/M transition and affects the polarization of M1 macrophages. SMOC2 controls MYO1C expression through ALKBH5-mediated m6A modification. In RA FLS, these genes promote FLS proliferation through different pathways. B METTL3 promotes FLS activation and inflammation through the NF-κB signaling pathway. METTL3 and YTHDF2 synergically inhibited the expression of PGC-1α and cytochrome C and reduced the ATP production and oxygen consumption rates. C In MH7A cells activated by TNF, the mRNA abundance and m6A methylation abundance of WTAP, RIPK2, JAK3, and TNFRSF10A significantly changed. These genes are involved in the pathogenesis of RA through m6A methylation. D The low expression of ALKBH5, FTO, and YTHDF2 in RA peripheral blood is associated with changes in inflammatory markers and some key pro-inflammatory cytokines. These genes may be biomarkers or predictors for the assessment of RA onset, disease progression, and disease severity

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