Multi-omics analysis reveals coordinated transcriptional and epigenetic remodeling of tenocytes under IL-1β-driven inflammatory stimulation
Abstract
Tendinopathy is frequently associated with chronic inflammation driven by pro-inflammatory cytokines. Among these, interleukin-1β (IL-1β) serves as a central mediator of tendon degradation, yet its genome-scale transcriptional and epigenetic consequences in tenocytes remain incompletely characterized. We profiled the transcriptomes and chromatin accessibility landscapes of control and IL-1β-treated primary rat tenocytes using RNA-seq and ATAC-seq, respectively. Differential expression and accessibility analyses, region-associated differentially expressed gene (RAD) analysis, gene functional enrichment analysis, and transcription factor motif enrichment analysis were performed to delineate the regulatory mechanisms underlying IL-1β-induced cellular response. IL-1β elicited a profound transcriptional alteration, with 1, 468 differentially expressed genes (811 upregulated and 657 downregulated). Upregulated genes were enriched for immune and inflammatory response pathways, whereas downregulated genes encompassed tendon-specific matrix programs and broader mesenchymal developmental pathways. Concordantly, ATAC-seq revealed 15, 257 differentially accessible regions, with a striking asymmetry toward increased accessibility under IL-1β treatment. Integrative analysis revealed a potential association between chromatin remodeling and transcriptional alterations. Motif enrichment within IL-1β-high accessible regions (IL-1β-HARs) identified C/EBP and NF-κB family members as candidate regulators of inflammatory gene activation, while control-HARs (Ctrl-HARs) harbored motifs for homeostatic transcription factors. These findings demonstrate that IL-1β affects tenocyte homeostasis by simultaneously activates inflammatory gene programs and suppresses tendon-associated expression through coordinated transcriptional and epigenetic remodeling. The transcription factor regulatory elements identified here provide a mechanistic hint for future investigation, and we hypothesize that targeting these elements may offer a potential therapeutic strategy for inflammatory tendon disorders, while this possibility remains to be tested experimentally.