Elucidating Epigenetic Regulation by Identifying Functional cis‐Acting Long Noncoding RNAs and Their Targets in Osteoarthritic Articular Cartilage
Arthritis & Rheumatology, vol. 72, pp. 1845–1854
Abstract
OBJECTIVE: To identify robustly differentially expressed long noncoding RNAs (lncRNAs) with osteoarthritis (OA) pathophysiology in cartilage and to explore potential target messenger RNA (mRNA) by establishing coexpression networks, followed by functional validation. METHODS: RNA sequencing was performed on macroscopically lesioned and preserved OA cartilage from patients who underwent joint replacement surgery due to OA (n = 98). Differential expression analysis was performed on lncRNAs that were annotated in GENCODE and Ensembl databases. To identify potential interactions, correlations were calculated between the identified differentially expressed lncRNAs and the previously reported differentially expressed protein-coding genes in the same samples. Modulation of chondrocyte lncRNA expression was achieved using locked nucleic acid GapmeRs. RESULTS: By applying our in-house pipeline, we identified 5,053 lncRNAs that were robustly expressed, of which 191 were significantly differentially expressed (according to false discovery rate) between lesioned and preserved OA cartilage. Upon integrating mRNA sequencing data, we showed that intergenic and antisense differentially expressed lncRNAs demonstrate high, positive correlations with their respective flanking sense genes. To functionally validate this observation, we selected P3H2-AS1, which was down-regulated in primary chondrocytes, resulting in the down-regulation of P3H2 gene expression levels. As such, we can confirm that P3H2-AS1 regulates its sense gene P3H2. CONCLUSION: By applying an improved detection strategy, robustly differentially expressed lncRNAs in OA cartilage were detected. Integration of these lncRNAs with differential mRNA expression levels in the same samples provided insight into their regulatory networks. Our data indicates that intergenic and antisense lncRNAs play an important role in regulating the pathophysiology of OA.
Authors 12
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Marcella van Hoolwerff Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Paula I. Metselaar Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Margo Tuerlings Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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H. Eka D. Suchiman Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Nico Lakenberg Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Y.F. Ramos Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Davy Cats Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Rob G. H. H. Nelissen Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Demiën Broekhuis Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Hailiang Mei Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Rodrigo Coutinho de Almeida Aachen
Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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