Genome‐Wide DNA Methylation Study Identifies Significant Epigenomic Changes in Osteoarthritic Cartilage

Abstract

Objective. To perform a genome-wide DNA methylation study to identify DNA methylation changes in osteoarthritic (OA) cartilage tissue.Methods. The contribution of differentially methylated genes to OA pathogenesis was assessed by bioinformatic analysis, gene expression analysis, and histopathologic severity correlation. Genome-wide DNA methylation profiling of >485,000 methylation sites was performed on eroded and intact cartilage from within the same joint of 24 patients undergoing hip arthroplasty for OA. Genes with differentially methylated CpG sites were analyzed to identify overrepresented gene ontologies, pathways, and upstream regulators. The messenger RNA expression of a subset of differentially methylated genes was analyzed by reverse transcription-polymerase chain reaction. Histopathology was graded by modified Mankin score and correlated with DNA methylation.Results. We identified 550 differentially methylated sites in OA. Most (69%) were hypomethylated and enriched among gene enhancers. We found differential methylation in genes with prior links to OA, including RUNX1, RUNX2, DLX5, FURIN, HTRA1, FGFR2, NFATC1, SNCAIP, and COL11A2. Among these, RUNX1, HTRA1, FGFR2, and COL11A2 were also differentially expressed. Furthermore, we found differential methylation in approximately one-third of known OA susceptibility genes. Among differentially methylated genes, upstream regulator analysis showed enrichment of TGFB1 (P ‫؍‬ 4.40 ؋ 10 ؊5 ) and several microRNAs including miR-128 (P ‫؍‬ 4.48 ؋ 10 ؊13 ), miR-27a (P ‫؍‬ 4.15 ؋ 10 ؊12 ), and miR-9 (P ‫؍‬ 9.20 ؋ 10 ؊10 ). Finally, we identified strong correlations between 20 CpG sites and the histologic Mankin score in OA.Conclusion. Our data implicate epigenetic dysregulation of a host of genes and pathways in OA, including a number of OA susceptibility genes. Furthermore, we identified correlations between CpG methylation and histologic severity in OA.

Renal involvement in lupus is characterized by unique DNA methylation changes in naïve CD4+ T cells

“…Mapping DNA methylation changes in health and disease can inform about disease-associated chromatin structure, and identify epigenetically modified genetic targets that can help to better understand disease pathogenesis and potentially identify novel targets for therapy [5,12–15]. Further, the dynamic nature of DNA methylation changes makes them appealing targets to explore as disease biomarkers [13,16].…”

Knee and hip articular cartilage have distinct epigenomic landscapes: implications for future cartilage regeneration approaches

“…Recent studies on genome-wide DNA methylation in AC have focused on either the knee12 23 or hip12 24 joints and more primarily on comparing OA affected with control tissues. Nevertheless, Rushton et al 12 did report epigenetic differences between knee and hip AC at specific CpGs.…”

DNA methyltransferase 3b regulates articular cartilage homeostasis by altering metabolism

“…DNMT1, however, is largely responsible for maintaining the DNA methylation signatures created by these de novo enzymes during cell division. Recent genome-wide methylation profiling studies have identified differentially methylated loci in the genome of human OA chondrocytes, thereby suggesting the involvement of DNMT-driven mechanisms in the development and/or progression of OA (18,(22)(23)(24)(25)(26). This study was designed to address the potential role of the de novo Dnmt3 enzymes in regulating murine articular cartilage homeostasis.…”