Decreased ALKBH5, FTO, and YTHDF2 in Peripheral Blood Are as Risk Factors for Rheumatoid Arthritis

Abstract

ALKBH5 (alkylation repair homolog protein 5), FTO (fat mass and obesity-associated protein), and RNA N6-methyladenosine (m6A) demethylase, are essential for the m6A mRNA modification. YTHDF2 (YT521-B homology domains 2) called m6A “readers” can recognize m6A modification. As the key enzymes of m6A methylation modification, ALKBH5, FTO, and YTHDF2 have been implicated in many diseases. However, little is known about the role of ALKBH5, FTO, and YTHDF2 in rheumatoid arthritis (RA). We measured the mRNA expression of ALKBH5, FTO, and YTHDF2 in RA patients and controls by quantitative real-time polymerase chain reaction, and the global m6A content was detected by an ELISA-like format. The mRNA expression of ALKBH5, FTO, and YTHDF2 in RA patients was further analyzed to investigate its correlations with disease activity. And, multivariate analysis (logistic regression) was used to analyze the risk factors. The mRNA expression of ALKBH5, FTO, and YTHDF2 in RA patients was significantly decreased compared to controls. The mRNA expression of ALKBH5 was significantly increased in RA patients that received regular treatment. The mRNA expression of FTO was associated with disease activity score 28 (DAS28), complement 3 (C3), immunoglobulin G (IgG), and lymphocyte-to-monocyte ratio (LMR), some common markers for RA disease activity. The mRNA expression of YTHDF2 was associated with RBC, L%, N%, NLR, and LMR. Furthermore, logistic regression analysis revealed that decreased expression of ALKBH5, FTO, and YTHDF2 in peripheral blood was a risk factor for RA. Moreover, the peripheral blood global m6A content was significantly increased in patients with RA compared to CON, and increased m6A contents negatively correlated with decreased mRNA expression of FTO. In conclusion, this study firstly demonstrates the critical role of ALKBH5, FTO, and YTHDF2 in RA, which provides novel insights into recognizing the pathogenesis of RA and a promising biomarker for RA.

Transcriptome-Wide High-Throughput m6A Sequencing of Differential m6A Methylation Patterns in the Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes Cell Line MH7A

“… 13 , 14 With the deepening of research and the rapid development of technology, it has been found that there is an association between m6A methylation and RA. Luo et al 15 confirmed that the expression of peripheral blood ALKBH5 and FTO was linked with autoantibody production and RA disease activity, which may be used as an indicator of activity and the inflammatory response. However, there are few studies about the effect of m6A methylation on RA FLSs.…”

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

“…These relatively weighty postulations suggesting detectable involvement of epitranscriptomics with the atherosclerosis-stimulated clonal hematopoiesis rest on several notions: (1) driver mutations for clonal hematopoiesis in HSCs, when present, often reside in epigenetic or epitranscriptomic targets [ 83 ], and (2) multiple governing enzymes of A-to-I [ 84 ] and m 6 A [ 31 , 85 , 86 , 87 , 88 ] have been shown to be essential for maintaining normal hematopoiesis. Finally, as proof-of-principles, emerging evidence suggests blood epitranscriptomes to act as potential source of biomarkers for coronary atherosclerosis and thus IHD [ 151 ], breast [ 165 ], gastric [ 166 ], and lung [ 167 ] cancers as well as for few other inflammation-centered pathologies than IHD, such as systemic lupus erythematosus [ 168 ] and rheumatoid arthritis [ 169 ].…”

Regulatory Role of the RNA N6-Methyladenosine Modification in Immunoregulatory Cells and Immune-Related Bone Homeostasis Associated With Rheumatoid Arthritis

“…YTHDF2 mRNA expression was shown to be correlated with L%, N%, RBC, NLR, and LMR. Moreover, logistic regression analysis suggested that reduced ALKBH5, FTO, and YTHDF2 expression in PBMCs is a risk factor for RA (Luo et al, 2020 ). Another study revealed that METTL3 expression is significantly increased in the PBMCs of RA patients (Wang J. et al, 2019 ).…”