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05.11 Antisense long noncoding rnas are deregulated in skin tissue of ssc patients
  1. Tobias Messemaker1,2,
  2. Loubna Chadli3,
  3. Varshna Goelela3,
  4. Maaike Boonstra1,
  5. Annemarie Dorjee1,
  6. Stefan Andersen3,
  7. Harald Mikkers2,
  8. Oliver Distler4,
  9. Tom Huizinga1,
  10. Zhenghui Li5,
  11. Guoshuai Cai5,
  12. Michael Whitfield5,
  13. Rene Toes1,
  14. Jamil Aarbiou3,
  15. Jeroen de Groot3,
  16. Jeska De Vries-Bouwstra1,
  17. Fina Kurreeman1
  1. 1Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
  2. 2Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands
  3. 3Charles River Nederland B.V., Leiden, The Netherlands
  4. 4Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  5. 5Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire USA

Abstract

Background Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis of skin and multiple organs of which pathogenesis is poorly understood. Here we studied differentially expressed coding and non-coding genes in relation to SSc pathogenesis with a specific focus on antisense non-coding RNAs.

Materials and methods Skin biopsy-derived RNAs from fourteen early SSc patients and six healthy individuals were sequenced with ion-torrent and analysed using DEseq2. Protein-coding and non-coding genes annotated in GENCODEV7 were analysed. Significant long non-coding RNAs were independently replicated in a Northern American dataset.

Results 4901 genes with a fold change >1.5 and a false discovery rate of less than 5% were detected in patients versus controls. Upregulated coding genes clustered in immunological, cell adhesion and keratin-related processes as previously found by microarray studies. Interestingly, 676 deregulated non-coding genes were detected, 257 of which were classified as antisense genes. 42% of these antisense genes had a concurrent deregulated sense gene. The majority of the sense-antisense genes had a similar effect sizes in an independent North American dataset with three genes (OTUD6B-AS1, CTBP1-AS2 and HMGN3-AS1) exceeding the study-wide Bonferroni-corrected ρ-value (PBonf <0.0024, Pcombined=1.6×10-9, 1.7 × 10–6, 2.6 × 10–6, respectively). Intriguingly, the correlation of sense-antisense gene pairs deregulated in SSc is stronger than sense-antisense gene pairs not deregulated in SSc (p<0.001).

Conclusions For the first time we highlight that together with coding genes, (antisense) long noncoding RNAs are deregulated in skin tissue of SSc patients suggesting a novel class of genes involved in pathogenesis of SSc.

Keywords
  • Systemic Sclerosis
  • RNA sequencing
  • antisense long noncoding RNAs.

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