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. 2022 Nov 16:9:959388.
doi: 10.3389/fmed.2022.959388. eCollection 2022.

The potential role of RNA N6-methyladenosine in primary Sjögren's syndrome

Qiufeng Xiao  1   2   3   4 , Xunyao Wu  5 , Chuiwen Deng  1   2   3   4 , Lidan Zhao  1   2   3   4 , Linyi Peng  1   2   3   4 , Jiaxin Zhou  1   2   3   4 , Wen Zhang  1   2   3   4 , Yan Zhao  1   2   3   4 , Yunyun Fei  1   2   3   4
Affiliations

The potential role of RNA N6-methyladenosine in primary Sjögren's syndrome

Qiufeng Xiao et al. Front Med (Lausanne). .

Erratum in

Abstract

Objective: The pathogenesis of primary Sjögren's syndrome (pSS) remains incompletely understood. The N6-methyladenosine (m6A) RNA modification, the most abundant internal transcript modification, has close associations with multiple diseases. This study aimed to investigate the role of m6A in patients with pSS.

Materials and methods: This study enrolled 44 patients with pSS, 50 age- and gender-matched healthy controls (HCs), and 11 age- and gender-matched patients with non-SS sicca. We detected the messenger RNA (mRNA) levels of m6A elements (including METTL3, WTAP, RBM15, ALKBH5, FTO, YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2), ISG15, and USP18 in peripheral blood mononuclear cells (PBMCs) from patients with pSS, patients with non-SS sicca, and HCs. The clinical characteristics and laboratory findings of patients with pSS and patients with non-SS sicca were also collected. We used binary logistic regression to determine if m6A elements were risk factors for pSS.

Results: The mRNA levels of m6A writers (METTL3 and RBM15), erasers (ALKBH5 and FTO), and readers (YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2) were all significantly higher in PBMCs from patients with pSS than in HCs. The mRNA levels of m6A writers (METTL3 and WTAP) and readers (YTHDF2, YTHDF3, and YTHDC2) were lower in PBMCs from patients with pSS compared to patients with non-SS sicca. The expression of METTL3, RBM15, FTO, YTHDF1, YTHDF2, YTHDC1, and YTHDC2 was positively correlated with the level of C-reactive protein (CRP) of patients with pSS. The mRNA level of YTHDF1 in PBMCs from patients with pSS was negatively correlated with the EULAR Sjögren's syndrome disease activity index (ESSDAI) score. In patients with pSS, FTO, YTHDC1, and YTHDC2 were also related to white blood cells (WBCs), neutrophils, lymphocytes, and monocytes. Increased mRNA level of ALKBH5 in PBMCs was a risk factor for pSS, as determined by binary logistic regression analysis. The mRNA level of ISG15 was positively correlated with that of FTO, YTHDF2, YTHDF3, and YTHDC2 in patients with pSS.

Conclusion: Compared with HCs, the expression of METTL3, RBM15, ALKBH5, FTO, YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 was considerably higher in PBMCs from patients with pSS. In comparison with patients with non-SS sicca, the expression of METTL3, WTAP, YTHDF2, YTHDF3, and YTHDC2 was reduced in PBMCs from patients with pSS. The m6A elements correlating with clinical variables may indicate the disease activity and inflammation status of pSS. Elevated expression of ALKBH5 was a risk factor for pSS. The dynamic process of m6A modification is active in pSS. m6A elements (FTO, YTHDF2, YTHDF3, or YTHDC2) might target ISG15, stimulate the expression of ISG15, and activate the type I IFN signaling pathway, playing an active role in initiating the autoimmunity in pSS.

Keywords: ALKBH5; ISG15; METTL3; N6-methyladenosine; YTHDF readers; primary Sjögren’s syndrome.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Messenger RNA (mRNA) levels of N6-methyladenosine (m6A) writers in peripheral blood mononuclear cells (PBMCs) from patients with primary Sjögren’s syndrome (pSS), patients with non-SS sicca, and healthy controls (HCs). (A,D) The mRNA level of METTL3 in PBMCs from patients with pSS was higher than that of HCs but lower than that of patients with non-SS sicca. (B,E) No significant difference was found in the expression of WTAP between patients with pSS and HCs. When compared to patients with non-SS sicca, the mRNA level of WTAP was decreased in patients with pSS. (C,F) The mRNA level of RBM15 in PBMCs from patients with pSS was higher than HCs. No significant difference was found in the expression of RBM15 between patients with pSS and patients with non-SS sicca. *p < 0.05, **p < 0.01, and ***p < 0.001.
FIGURE 2
FIGURE 2
Messenger RNA (mRNA) levels of N6-methyladenosine (m6A) erasers in peripheral blood mononuclear cells (PBMCs) from patients with primary Sjögren’s syndrome (pSS), patients with non-SS sicca, and healthy controls (HCs). (A,B) The mRNA levels of ALKBH5 and FTO in PBMCs from patients with pSS were higher than HCs. (C,D) No significant difference was found in the expression of ALKBH5 and FTO between patients with pSS and patients with non-SS sicca. **p < 0.01 and ***p < 0.001.
FIGURE 3
FIGURE 3
Messenger RNA (mRNA) levels of N6-methyladenosine (m6A) readers in peripheral blood mononuclear cells (PBMCs) from patients with primary Sjögren’s syndrome (pSS), patients with non-SS sicca, and healthy controls (HCs). (A–F) The mRNA levels of YTHDF2, YTHDF3, and YTHDC2 in PBMCs from patients with pSS were higher than that of HCs but lower than that of patients with non-SS sicca. (G–J) The mRNA levels of YTHDF1 and YTHDC1 in PBMCs from patients with pSS were higher than HCs. No significant difference was found in the expression of YTHDF1 and YTHDC1 between patients with pSS and patients with non-SS sicca. *p < 0.05, **p < 0.01, and ***p < 0.001.
FIGURE 4
FIGURE 4
Correlations between the expression of N6-methyladenosine-related genes and clinical data in patients with primary Sjögren’s syndrome (pSS). (A) METTL3 was positively correlated with C-reactive protein (CRP), immunoglobulin A (IgA), white blood cells, and neutrophils. WTAP was positively correlated with monocytes and antinuclear antibody (ANA). RBM15, YTHDF1, and YTHDF2 were positively correlated with CRP. FTO, YTHDC1, and YTHDC2 were positively correlated with CRP, white blood cells, neutrophils, lymphocytes, monocytes, and age. (B–F) Representative figures of positive correlations between m6A elements and clinical data in pSS. (G) The messenger RNA (mRNA) level of YTHDF1 was negatively correlated with the EULAR Sjögren’s syndrome disease activity index (ESSDAI) score. (H,I) No significant correlation was found between m6a elements and risk factors for the development of lymphoma in patients with pSS. CRP: C-reactive protein. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001.
FIGURE 5
FIGURE 5
Correlations between the expression of N6-methyladenosine-related genes and clinical data in patients with non-SS sicca. (A) The messenger RNA (mRNA) level of RBM15 was negatively correlated with lymphocyte%. (B) The mRNA level of YTHDF1 had a negative association with erythrocyte sedimentation rate (ESR). (C) The mRNA level of YTHDF3 had a positive association with complement 3 (C3). (D) The expression of YTHDC1 was negatively correlated with immunoglobulin A (IgA). ESR, erythrocyte sedimentation rate; C3, complement 3.
FIGURE 6
FIGURE 6
Correlations between the expression of N6-methyladenosine (m6A)-related genes and interferon-stimulated genes (ISGs) in primary Sjögren’s syndrome (pSS). (A–D) ISG15 was positively correlated with YTHDF2, YTHDF3, YTHDC2, and FTO in pSS. USP18 was not correlated with YTHDF2, YTHDF3, YTHDC2, and FTO in pSS.
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