Integrated multi-omics analysis identifies candidate eRNA-associated signatures shared between osteoarthritis and...

Area of Science:

• Molecular Biology
• Immunology
• Genomics

Background:

• Osteoarthritis (OA) and type 2 diabetes mellitus (T2DM) frequently coexist, sharing inflammatory and metabolic disturbances.
• Immune-epigenetic features linking OA and T2DM are not well understood.
• Enhancer RNAs (eRNAs) regulate gene expression, but their shared roles in OA and T2DM are unexplored.

Purpose of the Study:

• To investigate overlapping molecular features, particularly eRNA-associated signatures, between OA and T2DM.
• To identify candidate genes and transcriptional patterns involved in the immune-metabolic overlap of these conditions.

Main Methods:

• Analysis of transcriptomic datasets from OA joint tissues and T2DM monocytes.
• Utilized differential expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and CIBERSORT.
• Integrated public epigenomic (ATAC-seq, ChIP-seq) and single-cell RNA-seq data, alongside a high-glucose stress model in chondrocytes.

Main Results:

• Identified 473 dysregulated eRNA-associated features in OA, enriched in skeletal development and inflammatory pathways.
• Overlapping alterations in TNF-α/NF-κB and MAPK pathways were observed between OA and T2DM datasets.
• Prioritized TOB1 as a key eRNA-associated feature linked to JUN, CCNL1, and inflammatory signaling, with CCNL1 downregulated in both conditions.

Conclusions:

• TOB1 emerges as a critical eRNA-associated signal implicated in inflammatory signaling shared by OA and T2DM.
• Findings provide a framework for understanding immune-metabolic overlap, supported by epigenomic and in vitro data.
• Identified potential therapeutic targets for conditions with shared inflammatory and metabolic dysregulation.