A molecular map of long non-coding RNA expression, isoform switching and alternative splicing in osteoarthritis

Human Molecular Genetics, vol. 31, pp. 2090–2105

Abstract

Osteoarthritis is a prevalent joint disease and a major cause of disability worldwide with no curative therapy. Development of disease-modifying therapies requires a better understanding of the molecular mechanisms underpinning disease. A hallmark of osteoarthritis is cartilage degradation. To define molecular events characterizing osteoarthritis at the whole transcriptome level, we performed deep RNA sequencing in paired samples of low- and high-osteoarthritis grade knee cartilage derived from 124 patients undergoing total joint replacement. We detected differential expression between low- and high-osteoarthritis grade articular cartilage for 365 genes and identified a 38-gene signature in osteoarthritis cartilage by replicating our findings in an independent dataset. We also found differential expression for 25 novel long non-coding RNA genes (lncRNAs) and identified potential lncRNA interactions with RNA-binding proteins in osteoarthritis. We assessed alterations in the relative usage of individual gene transcripts and identified differential transcript usage for 82 genes, including ABI3BP, coding for an extracellular matrix protein, AKT1S1, a negative regulator of the mTOR pathway and TPRM4, coding for a transient receptor potential channel. We further assessed genome-wide differential splicing, for the first time in osteoarthritis, and detected differential splicing for 209 genes, which were enriched for extracellular matrix, proteoglycans and integrin surface interactions terms. In the largest study of its kind in osteoarthritis, we find that isoform and splicing changes, in addition to extensive differences in both coding and non-coding sequence expression, are associated with disease and demonstrate a novel layer of genomic complexity to osteoarthritis pathogenesis.

Authors 9

1. Georgia Katsoula

   Helmholtz Munich · Technical University of Munich

   Affiliation as printed

   Institute of Translational Genomics , Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany

   Technical University of Munich (TUM) , School of Medicine, Munich 81675, Germany

2. Julia Steinberg

   The University of Sydney · Helmholtz Munich · Cancer Council NSW

   Affiliation as printed

   Daffodil Centre, University of Sydney, a joint venture with Cancer Council NSW , Sydney, NSW 1340 , Australia

   Institute of Translational Genomics , Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany

3. Margo Tuerlings Aachen Section Molecular Epidemiology Department of Biomedical Data Sciences Section Molecular Epidemiology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Biomedical Data Sciences , Section Molecular Epidemiology, , Leiden 2333 ZC , The Netherlands

   Leiden University Medical Center , Section Molecular Epidemiology, , Leiden 2333 ZC , The Netherlands

   Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands

4. Rodrigo Coutinho de Almeida Aachen Section Molecular Epidemiology Department of Biomedical Data Sciences Section Molecular Epidemiology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Biomedical Data Sciences , Section Molecular Epidemiology, , Leiden 2333 ZC , The Netherlands

   Leiden University Medical Center , Section Molecular Epidemiology, , Leiden 2333 ZC , The Netherlands

   Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands

5. Lorraine Southam

   Helmholtz Munich

   Affiliation as printed

   Institute of Translational Genomics , Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany

6. Diane Swift

   Northern General Hospital · University of Sheffield

   Affiliation as printed

   Department of Oncology and Metabolism , , Sheffield, S5 7AU , UK

   University of Sheffield, Metabolic Bone Unit, Sorby Wing Northern General Hospital Sheffield , , Sheffield, S5 7AU , UK

   Department of Oncology and Metabolism, University of Sheffield, Metabolic Bone Unit, Sorby Wing Northern General Hospital Sheffield, Sheffield, S5 7AU, UK

7. Ingrid Meulenbelt Aachen Section Molecular Epidemiology Department of Biomedical Data Sciences Section Molecular Epidemiology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Biomedical Data Sciences , Section Molecular Epidemiology, , Leiden 2333 ZC , The Netherlands

   Leiden University Medical Center , Section Molecular Epidemiology, , Leiden 2333 ZC , The Netherlands

   Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands

8. Jeremy Mark Wilkinson corresponding

   Northern General Hospital · University of Sheffield

   Affiliation as printed

   Department of Oncology and Metabolism , , Sheffield, S5 7AU , UK

   University of Sheffield, Metabolic Bone Unit, Sorby Wing Northern General Hospital Sheffield , , Sheffield, S5 7AU , UK

   Department of Oncology and Metabolism, University of Sheffield, Metabolic Bone Unit, Sorby Wing Northern General Hospital Sheffield, Sheffield, S5 7AU, UK

9. Eleftheria Zeggini corresponding

   TUM Klinikum · Helmholtz Munich · Technical University of Munich

   Affiliation as printed

   Institute of Translational Genomics , Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany

   Technical University of Munich (TUM) and Klinikum Rechts der Isar , TUM School of Medicine, Munich 81675 , Germany