Dissertation committee:
Κουτσιλιέρης Μιχαήλ, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Σφηκάκης Πέτρος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κόλλιας Γεώργιος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Στέλλος Κωνσταντίνος, Καθηγητής, Faculty of Medical Sciences, Newcastle University, UK
Σταματελόπουλος Κίμων, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Τεκτονίδου Μαρία, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Σουλιώτης Βασίλειος, Διευθυντής Ερευνών, Ινστιτούτο Χημικής Βιολογίας, Εθνικό Ίδρυμα Ερευνών
Summary:
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 modifying selected nucleotides in RNA molecules. Herein, we tested the hypothesis that A-to-I RNA editing is altered in rheumatoid arthritis (RA). Synovial expression of ADAR1 and its isoforms, ADAR1p110 and ADAR1p150, was analysed in 152 RA patients and 50 controls. Peripheral blood mononuclear cells (PBMCs) 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 also involved in antigen presentation. ADAR1 was significantly over-expressed in RA synovium regardless of disease duration. Similarly, ADAR1p150 isoform expression was significantly increased in the synovium and blood of active RA patients, while ADAR1p110 levels were similar between patients and controls. Individual nucleotide analysis revealed that A-to-I RNA editing rate in cathepsin S AluSx+ was also significantly increased in RA patients. Both baseline ADAR1p150 expression and individual adenosine RNA editing rates in 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 was associated with a higher expression of edited Alu-enriched genes including cathepsin S and TNF receptor-associated factors 1,2,3 and 5. In conclusion, herein we describe a previously unrecognized regulation and role of ADAR1p150-mediated A-to-I RNA editing in post-transcriptional control of gene expression in RA, which underpins therapeutic response and fuels inflammatory gene expression, thus representing an interesting therapeutic target.
Keywords:
Rheumatoid Arthritis, ADAR1, A-to-I RNA editing, Alu elements, Cathepsin S
