Yehua Jin

Shanghai University of Traditional Chinese Medicine

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Cen Chang

Shanghai University of Traditional Chinese Medicine

Shicheng Guo

Shanghai University of Traditional Chinese Medicine

Lingxia Xu

Jiangsu University

Runrun Zhang

Zhejiang University

Linshuai Xu

Shanghai University of Traditional Chinese Medicine

Runrun Zhang

Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine

Dongyi He

Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine

Dongyi He

Shanghai University of Traditional Chinese Medicine

Steven J. Schrodi

University of Wisconsin–Madison

Kai Wei

Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine

Cooperative Institutions

Shanghai University of Traditional Chinese Medicine

Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine

Shanghai Innovative Research Center of Traditional Chinese Medicine

Fudan University

Chinese Academy of Sciences

Zhejiang University

Chinese Academy of Medical Sciences & Peking Union Medical College

Shanghai Jiao Tong University

Peking University

Wuhan University

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Biomarkers to Predict DMARDs Efficacy and Adverse Effect in Rheumatoid Arthritis

Frontiers in Immunology (2022)

Kai Wei Ping Jiang Jianan Zhao Yehua Jin Runrun Zhang

Rheumatoid arthritis (RA), one of the most common immune system diseases, mainly affects middle-aged and elderly individuals and has a serious impact on the quality of life of patients. Pain and disability caused by RA are significant symptoms negatively affecting patients, and they are especially seen when inappropriate treatment is administered. Effective therapeutic strategies have evolved over the past few decades, with many new disease-modifying antirheumatic drugs (DMARDs) being used in the clinic. Owing to the breakthrough in the treatment of RA, the symptoms of patients who could not be treated effectively in the past few years have been relieved. However, some patients complain about symptoms that have not been reported, implying that there are still some limitations in the RA treatment and evaluation system. In recent years, biomarkers, an effective means of diagnosing and evaluating the condition of patients with RA, have gradually been used in clinical practice to evaluate the therapeutic effect of RA, which is constantly being improved for accurate application of treatment in patients with RA. In this article, we summarize a series of biomarkers that may be helpful in evaluating the therapeutic effect and improving the efficiency of clinical treatment for RA. These efforts may also encourage researchers to devote more time and resources to the study and application of biomarkers, resulting in a new evaluation system that will reduce the inappropriate use of DMARDs, as well as patients’ physical pain and financial burden.

Antirheumatic drugs

10.3389/fimmu.2022.865267

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Epigenetic Regulation Mediated by Methylation in the Pathogenesis and Precision Medicine of Rheumatoid Arthritis

Lingxia Xu Shicheng Guo Cen Chang Runrun Zhang Yehua Jin

Rheumatoid arthritis (RA) as a complex disease is thought triggered by interaction between genetics and environment, especially the shared epitope (SE) and cell surface calreticulin (CSC) theory. However, all the evidence shows genetic diversity and environment exposure cannot explain all the clinical characteristics heterogeneity of rheumatoid arthritis. In contrast, recent studies demonstrate that epigenetics play important roles in the pathogenesis of rheumatoid arthritis, especially DNA methylation and histone modification. DNA methylation and histone methylation are involved in innate and adoptive immune cell differentiation and the migration, proliferation, apoptosis, and mesenchymal characteristics of fibroblast-like synoviocytes (FLS). Epigenetic mediated regulation to immune genes and inflammation pathway provides well explanation to dynamic expression network of rheumatoid arthritis. In this review, we summarized the comprehensive evidence to show methylation modification occurred in DNA and histone are significantly involved in the pathogenesis of rheumatoid arthritis and could be applied as the promising biomarker in the disease activity and drug response prediction. We also explained the opportunity and challenge of the current epigenetics research in rheumatoid arthritis. In summary, epigenetic modules provide possible interface through which genetic and environmental risk factors connect together to contribute to the susceptibility and pathogenesis of RA. Meanwhile epigenetic regulators provided promising drug targets to develop novel therapeutic drugs for rheumatoid arthritis. Finally, DNA methylation and histone modification will be important features to provide better rheumatoid arthritis subtype identification to accelerate personalized treatment and precision medicine.

Pathogenesis

10.20944/preprints202004.0237.v1

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RNA-Seq and Network Analysis Reveal Unique Chemokine Activity Gene Expression Signatures in Synovial Tissue From Rheumatoid Arthritis

Research Square (Research Square) (2021)

Runrun Zhang Yehua Jin Cen Chang Xinpeng Zhou Yanqin Bian

Abstract Objective: This study identified to provide a comprehensive understanding of genome-wide expression patterns of synovial tissue from rheumatoid arthritis (RA) patients to investigate the potential mechanism RA occurrence and development. Methods: The transcription profiles of 9 RA and 15 control (osteoarthritis OA) synovial tissue were generated by RNA-Seq. Gene set enrichment analysis (GSEA) was used to analyze all detected genes and differentially expressed genes (DEGs) were identified by DESeq. To further analyze the DEGs, Gene ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. The protein-protein interaction (PPI) network of DEGs were constructed by STRING and the hub genes were identified by topology clustering with MCODE-Cytoscape. The most important hub genes were validated by quantitative real time polymerase chain reaction (qRT-PCR). Results: A total of 17736 genes were detected and 651 DEGs were identified. For the GSEA, significantly enriched gene sets positively correlated with the RA group were CD40 signaling over-activation, Th1 cytotoxic module in C2, over-activation of immune response, adaptive immune response in C5, In C7, the up-regulation of the gene set of effective versus memory CD8 T cell is related to RA group. The down-regulation of gene set of naïve versus effective CD8 T cell is related to RA group.in C7. Biology process enrichment analysis showed that the DEGs were significantly enriched for signal transduction (P=1.52×10 -08 ), immune response (P=1.94×10 -22 ) and inflammatory response (P=1.11×10 -11 ). Molecule function enrichment analysis revealed over-represented calcium ion binding (P=8.61×10 -03 ), receptor binding (P=7.03×10 -05 ) and chemokine activity (P=4.15×10 -15 ). The DEGs were significantly enriched for plasma membrane (P=2.26×10 -20 ), integral component of membrane (P=7.79×10 -07 ), extracellular region (P=3.43×10 -16 ) in cellular component. The KEGG pathway analysis showed that the DEGs were enriched in the cytokine-cytokine receptor interaction (P=6.86×10 -21 ), chemokine signaling pathway (P=2.03×10 -11 ), systemic lupus erythematosus(P=9.23×10 -07 ), T cell receptor signaling pathway (P=6.59×10 -06 ) and rheumatoid arthritis (P=3.24×10 -05 ). We confirmed RA over-expressed PPI network hub genes included CXCL13 , CXCL6 , CCR5 , CXCR5 , CCR2 , CXCL3 , CXCL10 and RA down-regulated hub genes included SSTR1 . Conclusions: The study identified and verified the DEGs between RA and OA synovial tissue which highlighted the activity of a subset of chemokine genes, thereby providing novel insights into the molecular mechanisms of RA pathogenesis and identified potential diagnostic and therapeutic targets for RA.

KEGG

10.21203/rs.3.rs-510087/v1

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Therapeutic Effects of (5R)-5-Hydroxytriptolide on Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via lncRNA WAKMAR2/miR-4478/E2F1/p53 Axis

Frontiers in Immunology (2021)

Xinpeng Zhou Duoli Xie Jie Huang Aiping Lü Rongsheng Wang

Rheumatoid arthritis (RA) is an autoimmune disease. Fibroblast-like synoviocytes (FLS) serve a major role in synovial hyperplasia and inflammation in RA. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, shows promising therapeutic effects for RA and is now in phase II clinical trials in China. However, the underlying mechanism of LLDT-8 is still not fully understood. Here, we found that LLDT-8 inhibited proliferation and invasion of RA FLS, as well as the production of cytokines. Microarray data demonstrated that LLDT-8 upregulated the expression of long non-coding RNA (lncRNA) WAKMAR2, which was negatively associated with proliferation and invasion of RA FLS, as well as the production of pro-inflammatory cytokines. Knockdown of WAKMAR2 abolished the inhibitory effects of LLDT-8 on RA FLS. Mechanistically, WAKMAR2 sponged miR-4478, which targeted E2F1 and downstreamed p53 signaling. Rescue experiments indicated that the inhibitory effects of LLDT-8 on RA FLS were dependent on WAKMAR2/miR-4478/E2F1/p53 axis.

Triptolide

E2F1

10.3389/fimmu.2021.605616

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Identification of DNA methylation-regulated differentially expressed genes in RA by integrated analysis of DNA methylation and RNA-Seq data

Journal of Translational Medicine (2022)

Runrun Zhang Cen Chang Yehua Jin Lingxia Xu Ping Jiang

Abstract Objective To identify novel DNA methylation-regulated differentially expressed genes (MeDEGs) in RA by integrated analysis of DNA methylation and RNA-Seq data. Methods The transcription and DNA methylation profiles of 9 RA and 15 OA synovial tissue were generated by RNA-Seq and Illumina 850K DNA methylation BeadChip. Gene set enrichment analysis (GSEA) and Weighted gene co-expression network analysis (WGCNA) were used to analyze methylation-regulated expressed genes by R software. The differentially expressed genes (DEGs), differentially methylated probes (DMPs), differentially methylated genes (DMGs) were analyzed by DESeq and ChAMP R package. The functional correlation of MeDEGs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein–protein interaction (PPI) network of MeDEGs was constructed by STRING and Reactome FI Cytoscape Plugin. Correlation analysis between methylation level and mRNA expression was conducted with R software. Results A total of 17,736 genes, 25,578 methylated genes and 755,852 methylation probes were detected. A total of 16,421 methylation-regulated expressed genes were obtained. The GSEA showed that these genes are associated with activation of immune response, adaptive immune response, Inflammatory response in C5 (ontology gene sets). For KEGG analysis, these genes are associated with rheumatoid arthritis, NF-kappa B signaling pathway, T cell receptor signaling pathway. The WGCNA showed that the turquoise module exhibited the strongest correlation with RA (R = 0.78, P = 1.27 × 10 − 05 ), 660 genes were screened in the turquoise module. A total of 707 MeDEGs were obtained. GO analysis showed that MeDEGs were enriched in signal transduction, cell adhesion for BP, enriched in plasma membrane, integral component of membrane for CC, and enriched in identical protein binding, calcium ion binding for MF. The KEGG pathway analysis showed that the MeDEGs were enriched in calcium signaling pathway, T cell receptor signaling pathway, NF-kappa B signaling pathway, Rheumatoid arthritis. The PPI network containing 706 nodes and 882 edges, and the enrichment p value < 1.0 × 10 − 16 . With Cytoscape, based on the range of more than 10 genes, a total of 8 modules were screened out. Spearman correlation analysis showed RGS1(cg10718027), RGS1(cg02586212), RGS1(cg10861751) were significantly correlated with RA. Conclusions RGS1 can be used as novel methylated biomarkers for RA.

KEGG

Differentially methylated regions

10.1186/s12967-022-03664-5

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RNA-seq and Network Analysis Reveal Unique Chemokine Activity Signatures in the Synovial Tissue of Patients With Rheumatoid Arthritis

Frontiers in Medicine (2022)

Runrun Zhang Yehua Jin Cen Chang Lingxia Xu Yanqin Bian

This study aimed to provide a comprehensive understanding of the genome-wide expression patterns in the synovial tissue samples of patients with rheumatoid arthritis (RA) to investigate the potential mechanisms regulating RA occurrence and development.Transcription profiles of the synovial tissue samples from nine patients with RA and 15 patients with osteoarthritis (OA) (control) from the East Asian population were generated using RNA sequencing (RNA-seq). Gene set enrichment analysis (GSEA) was used to analyze all the detected genes and the differentially expressed genes (DEGs) were identified using DESeq. To further analyze the DEGs, the Gene Ontology (GO) functional enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. The protein-protein interaction (PPI) network of the DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and the hub genes were identified by topology clustering with the Molecular Complex Detection (MCODE)-Cytoscape. The most important hub genes were validated using quantitative real-time PCR (qRT-PCR).Of the 17,736 genes detected, 851 genes were identified as the DEGs (474 upregulated and 377 downregulated genes) using the false discovery rate (FDR) approach. GSEA revealed that the significantly enriched gene sets that positively correlated with RA were CD40 signaling overactivation, Th1 cytotoxic module, overactivation of the immune response, adaptive immune response, effective vs. memory CD8+ T cells (upregulated), and naïve vs. effective CD8+ T cells (downregulated). Biological process enrichment analysis showed that the DEGs were significantly enriched for signal transduction (P = 3.01 × 10-6), immune response (P = 1.65 × 10-24), and inflammatory response (P = 5.76 × 10-10). Molecule function enrichment analysis revealed that the DEGs were enriched in calcium ion binding (P = 1.26 × 10-5), receptor binding (P = 1.26 × 10-5), and cytokine activity (P = 2.01 × 10-3). Cellular component enrichment analysis revealed that the DEGs were significantly enriched in the plasma membrane (P = 1.91 × 10-31), an integral component of the membrane (P = 7.39 × 10-13), and extracellular region (P = 7.63 × 10-11). The KEGG pathway analysis showed that the DEGs were enriched in the cytokine-cytokine receptor interaction (P = 3.05 × 10-17), chemokine signaling (P = 3.50 × 10-7), T-cell receptor signaling (P = 5.17 × 10-4), and RA (P = 5.17 × 10-4) pathways. We confirmed that RA was correlated with the upregulation of the PPI network hub genes, such as CXCL13, CXCL6, CCR5, CXCR5, CCR2, CXCL3, and CXCL10, and the downregulation of the PPI network hub gene such as SSTR1.This study identified and validated the DEGs in the synovial tissue samples of patients with RA, which highlighted the activity of a subset of chemokine genes, thereby providing novel insights into the molecular mechanisms of RA pathogenesis and identifying potential diagnostic and therapeutic targets for RA.

KEGG

10.3389/fmed.2022.799440

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Epigenetic Regulation Mediated by microRNAs in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

Shicheng Guo Cen Chang Lingxia Xu Runrun Zhang Yehua Jin

MicroRNAs (miRNAs) play crucial roles in the regulation of the transcriptome and development of diseases including cancer and autoimmune diseases, such as rheumatoid arthritis (RA). Currently, a comprehensive map, illustrating how miRNAs regulate transcripts, pathways, immune system differentiation, and their interaction with terminal cells, such as T cells, fibroblast-like synoviocytes (FLS), osteoblasts, and osteoclasts, is still missing. In this review, we provide a thorough summary of the roles of miRNAs in the susceptibility to pathogenesis, diagnosis, therapeutic intervention, and prognosis of RA. Numerous miRNAs are abnormally expressed in cells involved in RA, and regulate target genes and pathways including the NF-κB, Fas-FasL, JAK-STAT, IRE1-RIDD, and mTOR pathways. By regulating gene expression, miRNAs affect T cell differentiation to diverse cell types, including Th17 and T-reg cells, and thus constitute promising gene therapy targets to modulate the immune system in RA. We summarize the diagnostic and prognostic potential of blood-circulating and cell-free miRNAs, highlighting the novel opportunities to combine these with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) to provide accurate diagnosis and prognosis, especially for seronegative patients. Furthermore, we outline how functional genetic variants of miR-499 and miR-146a partly explain the unmet susceptibility to RA. Additionally, we review the evidence implicating miRNAs as promising biomarkers of efficiency, response, and resistance to disease-modifying anti-rheumatic drugs (DMRDs) and immunotherapy. Finally, we discuss the autotherapeutic effect of miRNA intervention as a step toward the development of miRNA-based anti-RA drugs. Collectively, the current evidence supports miRNAs as interesting targets to better understand the pathogenetic mechanisms of RA and design more efficient therapeutic interventions.

Pathogenesis

10.20944/preprints202004.0241.v2

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LncRNA NONHSAT042241 inhibits rheumatoid synovial proliferation, inflammation and aggression via inactivating WNT/β-catenin signaling pathway

Autoimmunity (2024)

Yehua Jin Cen Chang Xinpeng Zhou Runrun Zhang Ping Jiang

This study aims to explore the effect of NONHSAT042241 on the function of rheumatoid arthritis -fibroblast-like synoviocyte (RA-FLS) and the underlying mechanisms.

Beta-catenin

10.1080/08916934.2024.2387076

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DNA methylation change of HIPK3 in Chinese rheumatoid arthritis and its effect on inflammation

Frontiers in Immunology (2023)

Ping Jiang Kai Wei Lingxia Xu Cen Chang Runrun Zhang

Homeodomain-interacting protein kinase 3 (HIPK3) plays an important role in cell proliferation, apoptosis, and inflammation. Over-expression of HIPK3 in immune cells in rheumatoid arthritis (RA) has been reported. In this study, we investigated blood methylation levels and clinical characteristics of RA in a Chinese population.

Rheumatoid factor

10.3389/fimmu.2022.1087279

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Citations (11)

MicroRNA variants and HLA-miRNA interactions are novel rheumatoid arthritis susceptibility factors

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Shicheng Guo Yehua Jin Jieru Zhou Qi Zhu Ting Jiang

Abstract Objective Althogh Genome-wide association studies have identified >100 variants for rheumatoid arthritis (RA),the reported genetic variants only explain <40% of RA heritability. We conducted a systemic association study between common East-Asian miRNA SNPs with RA in a large Han Chinese cohort to explain missing heritability and identify miRNA epistatic interactions. Methods 4 HLA SNPs (HLA-DRB1, HLA-DRB9, HLA-DQB1 and TNFAIP3) and 225 common SNPs located in miRNA which might influence the miRNA target binding or pre-miRNA stability were genotyped in 1,607 rheumatoid arthritis and 1,580 matched normal individuals. A meta-analysis with previous GWAS studies (4,873 RA cases and 17,642 controls) was performed to discovery another novel miRNA RA-associated SNPs. Results 2 novel SNPs including rs1414273 (miR-548ac, OR=0.84, P=8.26×10-4) and rs2620381 (miR-627, OR=0.77, P=2.55×10-3) conferred significant association with RA. Individuals carried 8 risk alleles showed 15.38 (95%CI: 4.69-50.49, P<1.0×10-6) times more risk to be affected by RA. In addition, rs5997893 (miR-3928) showed significant epistasis effect with rs4947332 (HLA-DRB1, OR=4.23, P=0.04) and rs2967897 (miR-5695) with rs7752903 (TNFAIP3, OR=4.43, P=0.03). Finally, we demonstrated targets of the significant miRNAs showed enrichment in immune related genes (P=2.0×10-5) and FDA approved drug target genes (P=0.014). Conclusions 6 novel miRNA SNPs including rs1414273 (miR-548ac, P=8.26×10-4), rs2620381 (miR-627, P=2.55×10-3), rs4285314 (miR-3135b, P=1.10×10-13), rs28477407 (miR-4308, P=3.44×10-5), rs5997893 (miR-3928, P=5.9×10-3) and rs45596840 (miR-4482, P=6.6×10-3) were confirmed to be significantly associated with RA in a Chinese population. Our study suggests that miRNAs might be interesting targets to accelerate the understanding of the pathogenesis and drug development for rheumatoid arthritis.

Genome-wide Association Study

SNP

Missing heritability problem

Genetic Association

Epistasis

10.1101/2020.08.25.264515

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Citations (3)