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A novel long non-coding RNA in the rheumatoid arthritis risk locus TRAF1-C5 influences C5 mRNA levels

Genes & Immunity volume 17, pages 85–92 (2016)Cite this article

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Abstract

Long non-coding RNAs (lncRNAs) can regulate the transcript levels of genes in the same genomic region. These locally acting lncRNAs have been found deregulated in human disease and some have been shown to harbour quantitative trait loci (eQTLs) in autoimmune diseases. However, lncRNAs linked to the transcription of candidate risk genes in loci associated to rheumatoid arthritis (RA) have not yet been identified. The TRAF1 and C5 risk locus shows evidence of multiple eQTLs and transcription of intergenic non-coding sequences. Here, we identified a non-coding transcript (C5T1lncRNA) starting in the 3′ untranslated region (UTR) of C5. RA-relevant cell types express C5T1lncRNA and RNA levels are further enhanced by specific immune stimuli. C5T1lncRNA is expressed predominantly in the nucleus and its expression correlates positively with C5 mRNA in various tissues (P=0.001) and in peripheral blood mononuclear cells (P=0.02) indicating transcriptional co-regulation. Knockdown results in a concurrent decrease in C5 mRNA levels but not of other neighbouring genes. Overall, our data show the identification of a novel lncRNA C5T1lncRNA that is fully located in the associated region and influences transcript levels of C5, a gene previously linked to RA pathogenesis.

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Acknowledgements

We wish to thank SJ Cramer and M. Rabelink for the generation of shRNA-containing lentiviral particles and H van Dam for providing reagents. We also thank the volunteers for donating blood and AWG Berendsen for experimental support. Finally we thank RC Hoeben and A Zaldumbide for comments and critical reading of the manuscript. This work was supported by the Dutch Arthritis Foundation, The Netherlands. F Kurreeman is supported via UNESCO-L’Oreal for Women in Science Fellowship, Marie Curie FP7 Outgoing Fellowship and an LUMC Research Fellowship.

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  1. H M M Mikkers and F Kurreeman: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Rheumatology, Leiden University Medical Centre, RC Leiden, The Netherlands

    T C Messemaker, R B Marques, A Adriaans, A M Bakker, N Daha, T W Huizinga, R E M Toes & F Kurreeman

  2. Department of Molecular Cell Biology, Leiden University Medical Centre, RC Leiden, The Netherlands

    T C Messemaker, A Adriaans & H M M Mikkers

  3. Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Schlieren, Switzerland

    M Frank-Bertoncelj & S Gay

  4. Department of Human Genetics, Leiden University Medical Centre, RC Leiden, The Netherlands

    F Kurreeman

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Messemaker, T., Frank-Bertoncelj, M., Marques, R. et al. A novel long non-coding RNA in the rheumatoid arthritis risk locus TRAF1-C5 influences C5 mRNA levels. Genes Immun 17, 85–92 (2016). https://doi.org/10.1038/gene.2015.54

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