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Integrative epigenomics, transcriptomics and proteomics of patient chondrocytes reveal genes and pathways involved in osteoarthritis

Julia Steinberg, Graham R. S. Ritchie, Theodoros I. Roumeliotis, Raveen L. Jayasuriya, Roger A. Brooks, Abbie L. A. Binch, Karan M. Shah, Rachael Coyle, Mercedes Pardo, Christine L. Le Maitre, Yolande F. M. Ramos, Rob G. H. H. Nelissen, Ingrid Meulenbelt, Andrew W. McCaskie, Jyoti S. Choudhary, J. Mark Wilkinson, Eleftheria Zeggini
doi: https://doi.org/10.1101/038067
Julia Steinberg
1Wellcome Trust Sanger Institute; Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA; UK
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Graham R. S. Ritchie
1Wellcome Trust Sanger Institute; Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA; UK
2European Molecular Biology Laboratory, European Bioinformatics Institute; Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD; UK
3Usher Institute of Population Health Sciences & Informatics; University of Edinburgh, Edinburgh, EH16 4UX; UK
4MRC Institute of Genetics & Molecular Medicine; University of Edinburgh; Edinburgh, EH4 2XU; UK
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Theodoros I. Roumeliotis
1Wellcome Trust Sanger Institute; Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA; UK
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Raveen L. Jayasuriya
5Department of Oncology and Metabolism; University of Sheffield; Beech Hill Road, Sheffield S10 2RX; UK
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Roger A. Brooks
6Division of Trauma & Orthopaedic Surgery; University of Cambridge; Box 180, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ; UK
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Abbie L. A. Binch
7Biomolecular Sciences Research Centre; Sheffield Hallam University; Sheffield, S1 1WB; UK
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Karan M. Shah
5Department of Oncology and Metabolism; University of Sheffield; Beech Hill Road, Sheffield S10 2RX; UK
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Rachael Coyle
1Wellcome Trust Sanger Institute; Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA; UK
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Mercedes Pardo
1Wellcome Trust Sanger Institute; Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA; UK
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Christine L. Le Maitre
7Biomolecular Sciences Research Centre; Sheffield Hallam University; Sheffield, S1 1WB; UK
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Yolande F. M. Ramos
8Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology; Leiden University Medical Center; Leiden, 2300RC; The Netherlands
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Rob G. H. H. Nelissen
9Department of Orthopedics; Leiden University Medical Center; Leiden, 2300RC; The Netherlands
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Ingrid Meulenbelt
8Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology; Leiden University Medical Center; Leiden, 2300RC; The Netherlands
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Andrew W. McCaskie
6Division of Trauma & Orthopaedic Surgery; University of Cambridge; Box 180, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ; UK
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Jyoti S. Choudhary
1Wellcome Trust Sanger Institute; Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA; UK
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J. Mark Wilkinson
5Department of Oncology and Metabolism; University of Sheffield; Beech Hill Road, Sheffield S10 2RX; UK
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Eleftheria Zeggini
1Wellcome Trust Sanger Institute; Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA; UK
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ABSTRACT

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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 30, 2016.
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Integrative epigenomics, transcriptomics and proteomics of patient chondrocytes reveal genes and pathways involved in osteoarthritis
Julia Steinberg, Graham R. S. Ritchie, Theodoros I. Roumeliotis, Raveen L. Jayasuriya, Roger A. Brooks, Abbie L. A. Binch, Karan M. Shah, Rachael Coyle, Mercedes Pardo, Christine L. Le Maitre, Yolande F. M. Ramos, Rob G. H. H. Nelissen, Ingrid Meulenbelt, Andrew W. McCaskie, Jyoti S. Choudhary, J. Mark Wilkinson, Eleftheria Zeggini
bioRxiv 038067; doi: https://doi.org/10.1101/038067
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Integrative epigenomics, transcriptomics and proteomics of patient chondrocytes reveal genes and pathways involved in osteoarthritis
Julia Steinberg, Graham R. S. Ritchie, Theodoros I. Roumeliotis, Raveen L. Jayasuriya, Roger A. Brooks, Abbie L. A. Binch, Karan M. Shah, Rachael Coyle, Mercedes Pardo, Christine L. Le Maitre, Yolande F. M. Ramos, Rob G. H. H. Nelissen, Ingrid Meulenbelt, Andrew W. McCaskie, Jyoti S. Choudhary, J. Mark Wilkinson, Eleftheria Zeggini
bioRxiv 038067; doi: https://doi.org/10.1101/038067

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