Increased adenosine-to-inosine RNA editing in rheumatoid arthritis

Abstract

Objective Adenosine-to-inosine (A-to-I) RNA editing of Alu retroelements is a primate-specific mechanism mediated by adenosine deaminases acting on RNA (ADARs) that diversifies transcriptome by changing selected nucleotides in RNA molecules. We tested the hypothesis that A-to-I RNA editing is altered in rheumatoid arthritis (RA). Methods Synovium expression analysis of ADAR1 was investigated in 152 RA patients and 50 controls. Peripheral blood mononuclear cells derived from 14 healthy subjects and 19 patients with active RA at baseline and after 12-week treatment were examined for ADAR1p150 and ADAR1p110 isoform expression by RT-qPCR. RNA editing activity was analysed by AluSx + Sanger-sequencing of cathepsin S, an extracellular matrix degradation enzyme involved in antigen presentation. Results ADAR1 was significantly over-expressed in RA synovium regardless of disease duration. Similarly, ADAR1p150 isoform expression was significantly increased in the blood of active RA patients. Individual nucleotide analysis revealed that A-to-I RNA editing rate was also significantly increased in RA patients. Both baseline ADAR1p150 expression and individual adenosine RNA editing rate of cathepsin S AluSx + decreased after treatment only in those patients with good clinical response. Upregulation of the expression and/or activity of the RNA editing machinery were associated with a higher expression of edited Alu -enriched genes including cathepsin S and TNF receptor-associated factors 1,2,3 and 5. Conclusion A previously unrecognized regulation and role of ADAR1p150-mediated A-to-I RNA editing in post-transcriptional control in RA underpins therapeutic response and fuels inflammatory gene expression, thus representing an interesting therapeutic target.

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

“…Peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll gradient centrifugation as previously described ( 31 ). Cells were resuspended in freezing medium [90% fetal bovine serum (FBS), 10% dimethyl sulfoxide (DMSO)] or lysed in TRIzol (Thermo Fisher Scientific, USA) and stored at -80°C until further processing.…”

Emerging Concepts and Challenges in Rheumatoid Arthritis Gene Therapy

“…The noncoding part of its mRNA demonstrated an increased number of A-to-I events in samples from patients with RA. Moreover, cathepsin S expression in the synovium was significantly increased in RA samples [167]. Interestingly, both ADAR expression and the individual adenosine RNA editing rate of cathepsin S decreased after treatment only in patients with a good clinical response to TNFis.…”

“…For example, modified ribonucleotides in siRNA evade immune response without loss of RNAi activity [166]. Recently, increased concentrations of adenosine deaminases acting on RNA (ADARs) were identified in the synovium of patients with RA [167]. Adenosine deamination results in the adenosine-to-inosine (A-to-I) editing event in mRNA and can modulate the level of protein expression.…”

Bioinformatics approaches for deciphering the epitranscriptome: Recent progress and emerging topics

“…For instance, A-to-I RNA editing activities have a significant diversity in response to different subtypes of influenza A virus in human epithelial cells [66] . A latest example found the regulatory role of the A-to-I RNA editing in the post-transcriptional control of rheumatoid arthritis (RA), which could be used in clinical treatment as a therapeutic target [67] . During the occurrence and development of human tumors, the A-to-I RNA editing level on some oncogenes and tumor suppressor genes also been found in disorder, but either high or low is contingent on the specific cancer type [58] , [68] , [69] .…”