Differential gene co-expression network analyses reveal novel molecules associated with transcriptional dysregulation of key biological processes in osteoarthritis knee cartilage()

OBJECTIVES: To compare co-expression networks of normal and osteoarthritis knee cartilage to uncover molecules associated with the transcriptional misregulation compromising biological processes (BPs) critical for cartilage homeostasis. DESIGN: Normal and osteoarthritis human knee cartilage RNA-seq GSE114007 dataset was obtained from the Gene Expression Omnibus database. Partial Correlation and Information Theory (PCIT) algorithm was used to build co-expression networks containing all nodes connecting to at least one differentially expressed gene (DEG) in normal and osteoarthritis networks. Hub and hub centrality genes were used to perform functional enrichment analysis. Enriched BPs known to be associated with both healthy and diseased cartilage were compared in depth. RESULTS: Differential co-expression network analyses allowed the identification of DDX43 and USP42 as exclusively co-expressed with DEGs in normal and osteoarthritis networks, respectively. The top hub and hub centrality genes of these networks were HIST1H3A and SNHG12 (normal) and TAF9B and OTUD1 (osteoarthritis). Enrichment analysis revealed several shared BPs between the contrasting groups, which are well-known in osteoarthritis pathogenesis. Protein-protein interaction network analysis for these BPs showed a global down-regulation of transcription factors in osteoarthritis. Specific transcription factors were identified as pleiotropic mediators in articular cartilage maintenance since they take part in several BPs. In addition, chromatin organisation and modification proteins were found relevant for osteoarthritis development. CONCLUSION: Differential gene co-expression analysis allowed the identification of novel and high priority therapeutic candidate genes that may drive modifications in the transcriptional “status” of cartilage in osteoarthritis.