Dynamic Editome of Zebrafish under Aminoglycosides Treatment and Its Potential Involvement in Ototoxicity.

Sijia Yan,Yulan Lu,Huizhong Zhu,Qinghe Xing,Weidong Tian,Lin He,Wei Cao,Menglin Jiang,Lihua Wu,Yu Su,Xinzhi Zhao

doi:10.3389/fphar.2017.00854

Abstract

RNA editing is an important co- and post-transcriptional event that generates RNA and protein diversity. Aminoglycosides are a group of bactericidal antibiotics and a mainstay of antimicrobial therapy for several life-threatening infections. However, aminoglycosides can induce ototoxicity, resulting in damage to the organs responsible for hearing and balance. At low concentrations, aminoglycosides can bind to many RNA sequences and critically influence RNA editing. We used a bioinformatics approach to investigate the effect of aminoglycosides on global mRNA editing events to gain insight into the interactions between mRNA editing and aminoglycoside ototoxicity. We identified 6,850 mRNA editing sites in protein coding genes in embryonic zebrafish, and in about 10% of these, the degree of RNA editing changed more than 15% under aminoglycosides treatment. Twelve ear-development or ototoxicity related genes, including plekhm1, fgfr1a, sox9a, and calrl2, exhibited remarkable changes in mRNA editing levels in zebrafish treated with aminoglycosides. Our results indicate that aminoglycosides may have a widespread and complicated influence on the progress of mRNA editing and expression. Furthermore, these results highlight the potential importance of mRNA editing in the pathogenesis and etiology of aminoglycoside-induced ototoxicity.

Highlights

RNA editing is a co- and post-transcriptional mechanism of introducing changes into RNA sequences encoded by the genomic blueprint
Our results provide a survey of the variation in mRNA editing rates after treatment with ototoxic drugs, such as AG
To establish a model of AG-induced ototoxicity, embryonic zebrafish were incubated in medium containing various concentrations of AG from the beginning of zebrafish ear development at the 50% epiboly/shield stage to 2 dpf, when the statoacoustic (VIIIth) ganglion becomes a separate section (Haddon and Lewis, 1996; Whitfield et al, 2002)

Summary

Introduction

RNA editing is a co- and post-transcriptional mechanism of introducing changes into RNA sequences encoded by the genomic blueprint. The most common type of RNA editing in metazoans is the conversion of adenosine to inosine, which is translated as guanosine [A-to-I (G)] This change is carried out by adenosine deaminases that act on RNA (ADARs) proteins, a family of double stranded RNA (dsRNA) binding enzymes. A-to-I (G) editing sites are mostly located in Alu repeats, and are essential for the normal physiology of cells (Wang et al, 2013; Porath et al, 2014) This mechanism is not static, and shows continuous dynamic change in different tissues and development stages to fine-tune and optimize biological pathways (Mehler and Mattick, 2007; Hwang et al, 2016; Qiu et al, 2016)

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Discussion

Conclusion