Dengue virus infection alters post-transcriptional modification of microRNAs in the mosquito vector Aedes aegypti.

Kayvan Etebari,Solomon Osei-Amo,Sassan Asgari,Simon Phillip Blomberg

doi:10.1038/srep15968

Abstract

Recent discoveries regarding the importance of isomiRs have increased our understanding of the regulatory complexities of the miRNAome. Observed changes in the miRNA profiles in mosquitoes infected with flaviviruses have implicated small RNAs in the interactions between viruses and their vectors. Here we analysed the isomiR profiles of both uninfected and infected Aedes aegypti mosquitoes with the major human pathogen dengue virus (DENV). We found that several specific isomiRs were significantly altered in their abundance patterns in response to DENV infection potentially affecting their target repertoire. Notable among these were isomiR variants which displayed arm-switching. We also demonstrate that modifications to the 3p end of miRNAs are vastly more prevalent than those at the 5p ends. We also observed that in only 45% of Ae. aegypti miRNAs the most abundant read matches the exact sequence reported in miRBase. Further, we found positive correlations between the number of mature miRNA reads, pre-miRNA length, GC content and secondary structure minimum free energy with the number of isomiRs. The findings presented here provide some evidence that isomiR production is not a random phenomenon and may be important in DENV replication in its vector.

Highlights

Recent discoveries regarding the importance of isomiRs have increased our understanding of the regulatory complexities of the miRNAome
When the substantial over-representation of 3′ modifications is taken into account, it is apparent that other factors contribute to the production of isomiRs
We explored the sequence variation of mapped reads correlating with Ae. aegypti miRNAs in dengue virus (DENV)-infected and uninfected mosquitoes

Summary

Introduction

Recent discoveries regarding the importance of isomiRs have increased our understanding of the regulatory complexities of the miRNAome. Despite being largely more frequent at the 3′ end, these variations can occur at both ends of the miRNA sequence and can even be present in the form of nucleotide substitutions[10,16,17,18] It is poorly understood how the production of isomiRs is regulated but there have been several proposed mechanisms as to the mode of their biogenesis, which has been demonstrated to be complex and even cell type specific[9,19]. Little is known about the mechanisms responsible for 5′ miRNA modifications, in Caenorhabditis elegans, modifications to the 5′ end which destabilize miRNAs and contribute to their degradation in vivo have been shown to be enacted by the exoribonuclease XRN-210 Despite their biogenesis being poorly understood, 5′ modifications to miRNAs are potentially crucially important given the tendency of particular base changes at the 5′ nucleotide to dictate which of the varying Ago proteins that a specific miRNA will bind to[26,27]

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Conclusion