Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: The “interferon signature”, marked by transcriptional upregulation of interferon (IFN)-inducible (IFI) genes, is a common finding in Sjögren’s syndrome (SS) that is associated with anti-Ro production. Recent studies have implicated long non-coding RNAs (lncRNAs) as novel transcriptional regulators of IFI genes, yet their contribution to dysregulated IFN responses in SS remains unknown. In this study, we used RNA sequencing (RNA-seq) to characterize the relationship between lncRNAs and IFN transcriptional responses in anti-Ro-positive SS (SSRo+) and to prioritize lncRNAs for functional evaluation.
Methods: We used RNA-seq to generate whole-blood transcriptional profiles for 27 SSRo+ patients and 27 healthy controls (HCs). Sequences were aligned to the human genome using TOPHAT and identified differentially expressed (DE) transcripts (FC >2 or <0.5 and q<0.05) using DEseq. For those DE IFI transcripts with a coefficient of variation (CV) >100% from a subset of 64 IFI transcripts, we calculated Pearson’s correlation statistic, r, against the 267 DE antisense and 793 DE long-intergenic non-coding RNAs and identified those showing positive (r >+0.70) and negative (r <-0.60) correlation with FDR-corrected significance <0.05. To confirm DE of specific targets, we utilized qRT-PCR in an independent cohort of 16 SSRo+cases and 36 HCs to determine the relative expression of specific transcripts. Statistical significance was determined using an unpaired t-test in Prism.
Results: For the 19 DE IFI transcripts with CV>100%, we identified 6 DE lncRNAs whose expression is significantly correlated with IFI transcripts, including both overexpressed [MX1-AS1 (FC=4.12), OAS123-AS1 (FC=3.35), NRIR (FC=2.73), GBP5-AS1 (FC=2.51)] and underexpressed [ERC1-AS1 (FC=0.45), linc-DCP1B (FC=0.50)] lncRNAs. For only the overexpressed lncRNAs, we noted correlated expression with DE IFI genes in their immediate proximity, such as MX1-AS1 (MX1, r =0.95), OAS123-AS1 (OAS1, r=0.92; OAS2, r=0.91; OAS3, r=0.86), NRIR (RSAD2, r=0.77; CMPK2, r=0.80), and GBP5-AS1 (GBP5, r=0.96). We have replicated the finding of NRIR upregulation in an independent cohort of SSRo+ cases and HCs (p=4.8×10-3), and replication is in progress for the remaining targets.
Conclusion: In this study, we have identified 6 novel SS lncRNAs showing significant co-expression with transcripts found within the IFN signature. Previous studies have implicated NRIR in the negative regulation of a subset of IFI genes that include the neighboring genes RSAD2 and CMPK2. The proximity of additional overexpressed lncRNAs to well-defined IFI genes known to be dysregulated in SS and other autoimmune disorders bolsters the argument that these lncRNAs have regulatory roles and mediate IFI transcriptional responses. Further elucidation of the relationship between lncRNAs and expression differences in both peripheral blood and exocrine gland tissue has the potential to identify peripheral biomarkers that define specific clinical and transcriptional features resulting from IFI gene dysregulation.
To cite this abstract in AMA style:Ice JA, Adrianto I, Joachims ML, Kelly JA, Wiley GB, Rasmussen A, Grundahl K, Houston GD, Lewis DM, Radfar L, Stone DU, Guthridge JM, Segal BM, Rhodus NL, Chodosh J, Gopalakrishnan R, Huang AJW, Hughes PJ, Rohrer MD, James JA, Montgomery CG, Scofield RH, Gaffney P, Sivils KL, Lessard CJ. Identification of Sjogren’s Syndrome-Associated Long Non-Coding RNAs That Are Co-Expressed with Key Protein-Coding Transcripts Involved in Dysregulated Interferon Responses [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/identification-of-sjogrens-syndrome-associated-long-non-coding-rnas-that-are-co-expressed-with-key-protein-coding-transcripts-involved-in-dysregulated-interferon-responses/. Accessed May 21, 2019.
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