Dataset Information

DNA methylation is involved in the pathogenesis of osteoarthritis by regulating CtBP expression and CtBP-mediated signaling.

ABSTRACT: Osteoarthritis (OA) is a common type of arthritis. Chronic inflammation is an important contributor to the pathogenesis of OA. The maturation and secretion of proinflammatory cytokines are controlled by inflammasomes, especially NLRP1 (NLR Family Pyrin Domain Containing 1) and NLRP3. In this study, we identified a transactivation mechanism of NLRP3 mediated by CtBPs (C-terminal-binding proteins). We found that both the mRNA and protein levels of CtBPs were significantly increased in OA biopsies. Analyzing the profiles of differentially expressed genes in CtBP-knockdown and overexpression cells, we found that the expression of NLRP3 was dependent on CtBP levels. By the knockdown or overexpression of transcription factors that potentially bind to the promoter of NLRP3, we found that only AP1 could specifically regulate the expression of NLRP3. Using immunoprecipitation (IP) and Co-IP assays, we found that AP1 formed a transcriptional complex with a histone acetyltransferase p300 and CtBPs. The knockdown of any member of this transcriptional complex resulted in a decrease in the expression of NLRP3. To explore the underlying mechanism of CtBP overexpression, we analyzed their promoters and found that they were abundant in CpG islands. Treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (AZA) or knockdown of DNMTs (DNA methyltransferases) resulted in the overexpression of CtBPs, while overexpression of DNMTs caused the reverse effects on CtBP expression. Collectively, our results suggest that the decreased DNA methylation levels in the promoters of CtBPs upregulate their expression. Increased CtBPs associated with p300 and AP1 to form a transcriptional complex and activate the expression of NLRP3 and its downstream signaling, eventually aggravating the inflammatory response and leading to the pathogenesis of OA.

SUBMITTER: Sun X

PROVIDER: S-EPMC7053340 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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DNA methylation is involved in the pathogenesis of osteoarthritis by regulating <i>CtBP</i> expression and CtBP-mediated signaling.

Sun Xiangxiang X Xiao Lin L Chen Juan J Chen Xun X Chen Xinlin X Yao Shuxin S Li Hui H Zhao Guanghui G Ma Jianbing J

International journal of biological sciences 20200130 6

Osteoarthritis (OA) is a common type of arthritis. Chronic inflammation is an important contributor to the pathogenesis of OA. The maturation and secretion of proinflammatory cytokines are controlled by inflammasomes, especially NLRP1 (NLR Family Pyrin Domain Containing 1) and NLRP3. In this study, we identified a transactivation mechanism of <i>NLRP3</i> mediated by CtBPs (C-terminal-binding proteins). We found that both the mRNA and protein levels of CtBPs were significantly increased in OA bi ...[more]

PMID: 32140068

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Project description:Osteoarthritis (OA) is chronic arthritis characterized by articular cartilage degradation. However, a comprehensive regulatory network for OA-related microRNAs and DNA methylation modifications has yet to be established. Thus, we aimed to identify epigenetic changes in microRNAs and DNA methylation and establish the regulatory network between miRNAs and DNA methylation. The mRNA, miRNA, and DNA methylation expression profiles of healthy or osteoarthritis articular cartilage samples were downloaded from Gene Expression Omnibus (GEO) database, including GSE169077, GSE175961, and GSE162484. The differentially expressed genes (DEGs), differentially expressed miRNAs (DEMs), and differentially methylated genes (DMGs) were analyzed by the online tool GEO2R. DAVID and STRING databases were applied for functional enrichment analysis and protein-protein interaction (PPI) network. Potential therapeutic compounds for the treatment of OA were identified by Connectivity map (CMap) analysis. A total of 1424 up-regulated DEGs, 1558 down-regulated DEGs, 5 DEMs with high expression, 6 DEMs with low expression, 1436 hypermethylated genes, and 455 hypomethylated genes were selected. A total of 136 up-regulated and 65 downregulated genes were identified by overlapping DEGs and DEMs predicted target genes which were enriched in apoptosis and circadian rhythm. A total of 39 hypomethylated and 117 hypermethylated genes were obtained by overlapping DEGs and DMGs, which were associated with ECM receptor interactions and cellular metabolic processes, cell connectivity, and transcription. Moreover, The PPI network showed COL5A1, COL6A1, LAMA4, T3GAL6A, and TP53 were the most connective proteins. After overlapping of DEGs, DMGs and DEMs predicted targeted genes, 4 up-regulated genes and 11 down-regulated genes were enriched in the Axon guidance pathway. The top ten genes ranked by PPI network connectivity degree in the up-regulated and downregulated overlapping genes of DEGs and DMGs were further analyzed by the CMap database, and nine chemicals were predicted as potential drugs for the treatment of OA. In conclusion, TP53, COL5A1, COL6A1, LAMA4, and ST3GAL6 may play important roles in OA genesis and development.

Project description:Osteoarthritis (OA) is a common type of arthritis, which may cause pain and disability. Alterations in gene expression and DNA methylation have been proven to be associated with the development of OA. The aim of the present study was to identify potential therapeutic targets and associated processes for OA via the combined analysis of gene expression and DNA methylation datasets. The gene expression and DNA methylation profiles were obtained from the Gene Expression Omnibus, and differentially expressed genes (DEGs) and differentially methylated sites (DMSs) were identified in the present study, using R programming software. The enriched functions of DEGs and DMSs were obtained via the Database for Annotation, Visualization and Integrated Discovery. Finally, cross analysis of DEGs and DMSs was performed to identify genes that exhibited differential expression and methylation simultaneously. The protein?protein interaction (PPI) network of overlaps between DEGs and DMSs was obtained using the Human Protein Reference Database; the topological properties of PPI network overlaps were additionally obtained. Hub genes in the PPI network were further confirmed via reverse transcription?quantitative polymerase chain reaction (RT?qPCR). The results of the present study revealed that the majority of DEGs and DMSs were upregulated and hypomethylated in patients with OA, respectively. DEGs and DMSs were primarily involved in inflammatory, immune and gene expression regulation?associated processes and pathways. Cross analysis revealed 30 genes that exhibited differential expression and methylation in OA simultaneously. Topological analysis of the PPI network revealed that numerous genes, including G protein subunit ?1 (GNAI1), runt related transcription factor 2 (RUNX2) and integrin subunit ?2 (ITGB2), may be involved in the development of OA. Additionally, RT?qPCR analysis of GNAI1, RUNX2 and ITGB2 provided further confirmation. Numerous known and novel therapeutic targets were obtained via network analysis. The results of the present study may be beneficial for the diagnosis and treatment of OA.

Dataset Information

DNA methylation is involved in the pathogenesis of osteoarthritis by regulating CtBP expression and CtBP-mediated signaling.

Publications

DNA methylation is involved in the pathogenesis of osteoarthritis by regulating <i>CtBP</i> expression and CtBP-mediated signaling.

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