Diagnostic gene signatures and aberrant pathway activation based on m6A methylation regulators in rheumatoid arthritis

Geng, Qishun; Cao, Xiaoxue; Fan, Danping; Gu, Xiaofeng; Zhang, Qian; Zhang, Mengxiao; Wang, Zheng; Deng, Tingting; Xiao, Cheng

doi:10.3389/fimmu.2022.1041284

Cited by 14 publications

(8 citation statements)

References 38 publications

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“…Several studies have investigated the role of IGF2BP3 in modulating macrophage phenotype, while the results have been conflicting. Some researchers claimed that IGF2BP3 promotes proinflammatory M1 macrophage polarization, while others deemed it to enhance M2 subtype shifting [ 80 , 81 ]. In our study, we found IGF2BP3 overexpressed BMDMs polarized into the M1 phenotype and secreted more inflammatory cytokines, whereas IGF2BP3 knockdown led to M2 polarization and inhibited inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Ni et al analyzed the expression levels of 23 m6A regulators in OA chondrocytes and identified YTHDF3 and IGF2BP3 as upregulated m6A readers in OA chondrocytes and may be correlated with enhanced chondrocyte ECM catabolism [ 30 ]. Zhao et al found that IGF2BP3 is enhanced in the synovium of patients with RA and is a potential regulator of inflammation-related pathways [ 80 ]. Xiong et al identified 12 differentially expressed m6A genes in the OA synovium based on RNA-seq data from 10 normal and 10 OA samples, including IGF2BP3 [ 82 ].…”

Section: Discussionmentioning

confidence: 99%

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Expression pattern analysis of m6A regulators reveals IGF2BP3 as a key modulator in osteoarthritis synovial macrophages

Pan

Zhang

et al. 2023

J Transl Med

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Background Disruption of N6 methyl adenosine (m6A) modulation hampers gene expression and cellular functions, leading to various illnesses. However, the role of m6A modification in osteoarthritis (OA) synovitis remains unclear. This study aimed to explore the expression patterns of m6A regulators in OA synovial cell clusters and identify key m6A regulators that mediate synovial macrophage phenotypes. Methods The expression patterns of m6A regulators in the OA synovium were illustrated by analyzing bulk RNA-seq data. Next, we built an OA LASSO-Cox regression prediction model to identify the core m6A regulators. Potential target genes of these m6A regulators were identified by analyzing data from the RM2target database. A molecular functional network based on core m6A regulators and their target genes was constructed using the STRING database. Single-cell RNA-seq data were collected to verify the effects of m6A regulators on synovial cell clusters. Conjoint analyses of bulk and single-cell RNA-seq data were performed to validate the correlation between m6A regulators, synovial clusters, and disease conditions. After IGF2BP3 was screened as a potential modulator in OA macrophages, the IGF2BP3 expression level was tested in OA synovium and macrophages, and its functions were further tested by overexpression and knockdown in vitro. Results OA synovium showed aberrant expression patterns of m6A regulators. Based on these regulators, we constructed a well-fitting OA prediction model comprising six factors (FTO, YTHDC1, METTL5, IGF2BP3, ZC3H13, and HNRNPC). The functional network indicated that these factors were closely associated with OA synovial phenotypic alterations. Among these regulators, the m6A reader IGF2BP3 was identified as a potential macrophage mediator. Finally, IGF2BP3 upregulation was verified in the OA synovium, which promoted macrophage M1 polarization and inflammation. Conclusions Our findings revealed the functions of m6A regulators in OA synovium and highlighted the association between IGF2BP3 and enhanced M1 polarization and inflammation in OA macrophages, providing novel molecular targets for OA diagnosis and treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Expression pattern analysis of m6A regulators reveals IGF2BP3 as a key modulator in osteoarthritis synovial macrophages

Pan

Zhang

et al. 2023

J Transl Med

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“…These findings provide novel sights for developing clinical treatment strategies targeting METTL3, METTL14 and ALKBH5. In addition, through systemically analyzing the roles of m6A modifications in RA based on gene expression profiling data, novel targets were identified for RA clinical diagnosis and therapy, such as, Geng et al found that IGF2BP3 and YTHDC2 could be used to diagnose RA accurately [ 112 ]. Besides, WTAP was involved in the m6A modification of ETS1 and regulated the macrophage polarization progression in RA [ 113 ].…”

Section: M6a and Skeletal System Diseasementioning

confidence: 99%

Recent advances of m6A methylation in skeletal system disease

Liang,

Yi,

Liu

et al. 2024

J Transl Med

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Skeletal system disease (SSD) is defined as a class of chronic disorders of skeletal system with poor prognosis and causes heavy economic burden. m6A, methylation at the N6 position of adenosine in RNA, is a reversible and dynamic modification in posttranscriptional mRNA. Evidences suggest that m6A modifications play a crucial role in regulating biological processes of all kinds of diseases, such as malignancy. Recently studies have revealed that as the most abundant epigentic modification, m6A is involved in the progression of SSD. However, the function of m6A modification in SSD is not fully illustrated. Therefore, make clear the relationship between m6A modification and SSD pathogenesis might provide novel sights for prevention and targeted treatment of SSD. This article will summarize the recent advances of m6A regulation in the biological processes of SSD, including osteoporosis, osteosarcoma, rheumatoid arthritis and osteoarthritis, and discuss the potential clinical value, research challenge and future prospect of m6A modification in SSD.

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“…In RA FLS, siIGF2BP3 decreased the expression of cyclin B1 (CCNB1) and cellular myelocytomatosis viral oncogene (c-Myc). IGF2BP3 can regulate the G2/M transition, promote the proliferation of RA FLS, and affect the polarization of M1 macrophages [ 38 ]. However, it remains to be confirmed how IGF2BP3 regulates macrophage polarization and inflammatory deterioration during RA progression through CCNB1 and c-Myc.…”

Section: M6a Methylation In Ramentioning

confidence: 99%

“… [ 37 ] RA IGF2BP3 Reader Synovial tissues Up-regulation Regulates the G2/M transition and affects the polarization of M1 macrophages. [ 38 ] RA SMOC2 - Synovial tissues Up-regulation Controls MYO1C expression through ALKBH5-mediated m6A modification. [ 40 ] RA METTL3 Writer PBMC Up-regulation Attenuated LPS-induced inflammatory response in macrophages via the NF-κB signaling pathway.…”

Section: M6a Methylation In Other Autoimmune Diseasesmentioning

confidence: 99%

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

Huang,

Xue,

Chang

et al. 2023

Arthritis Res Ther

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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.

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Diagnostic gene signatures and aberrant pathway activation based on m6A methylation regulators in rheumatoid arthritis

Cited by 14 publications

References 38 publications

Expression pattern analysis of m6A regulators reveals IGF2BP3 as a key modulator in osteoarthritis synovial macrophages

Expression pattern analysis of m6A regulators reveals IGF2BP3 as a key modulator in osteoarthritis synovial macrophages

Recent advances of m6A methylation in skeletal system disease

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

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