TY - JOUR T1 - Integrative epigenomics, transcriptomics and proteomics of patient chondrocytes reveal genes and pathways involved in osteoarthritis JF - bioRxiv DO - 10.1101/038067 SP - 038067 AU - Julia Steinberg AU - Graham R. S. Ritchie AU - Theodoros I. Roumeliotis AU - Raveen L. Jayasuriya AU - Roger A. Brooks AU - Abbie L. A. Binch AU - Karan M. Shah AU - Rachael Coyle AU - Mercedes Pardo AU - Christine L. Le Maitre AU - Yolande F. M. Ramos AU - Rob G. H. H. Nelissen AU - Ingrid Meulenbelt AU - Andrew W. McCaskie AU - Jyoti S. Choudhary AU - J. Mark Wilkinson AU - Eleftheria Zeggini Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/11/30/038067.abstract N2 - Background Osteoarthritis (OA) is a common disease characterized by cartilage degeneration and joint remodeling. The underlying molecular changes underpinning disease progression are incompletely understood, but can be characterized using recent advances in genomics technologies, as the relevant tissue is readily accessible at joint replacement surgery. Here we investigate genes and pathways that mark OA progression, combining genome-wide DNA methylation, RNA sequencing and quantitative proteomics in isolated primary chondrocytes from matched intact and degraded articular cartilage samples across twelve patients with OA undergoing knee replacement surgery.Results We identify 49 genes differentially regulated between intact and degraded cartilage at multiple omics levels, 16 of which have not previously been implicated in OA progression. Using independent replication datasets, we replicate statistically significant signals and show that the direction of change is consistent for over 90% of differentially expressed genes and differentially methylated CpG probes. Three genes are differentially regulated across all 3 omics levels: AQP1, COL1A1 and CLEC3B, and all three have evidence implicating them in OA through animal or cellular model studies. Integrated pathway analysis implicates the involvement of extracellular matrix degradation, collagen catabolism and angiogenesis in disease progression. All data from these experiments are freely available as a resource for the scientific community.Conclusions This work provides a first integrated view of the molecular landscape of human primary chondrocytes and identifies key molecular players in OA progression that replicate across independent datasets, with evidence for translational potential. ER -