Redirection of Silencing Targets by Adenosine-to-Inosine Editing of miRNAs

TLDR

Certain miRNA genes undergo adenosine‑to‑inosine RNA editing, but its functional significance remains largely unknown. The study reports that tissue‑specific A‑to‑I editing of miR‑376 cluster transcripts results in predominant expression of edited miR‑376 isoforms. The editing occurs at a highly edited site within the 5′ seed region of miR‑376, altering its target‑binding specificity. The edited miR‑376 RNA silences a distinct set of genes, including phosphoribosyl pyrophosphate synthetase 1, thereby regulating uric‑acid levels and revealing a novel role for RNA editing in miRNA‑mediated gene silencing.

Abstract

Primary transcripts of certain microRNA (miRNA) genes are subject to RNA editing that converts adenosine to inosine. However, the importance of miRNA editing remains largely undetermined. Here we report that tissue-specific adenosine-to-inosine editing of miR-376 cluster transcripts leads to predominant expression of edited miR-376 isoform RNAs. One highly edited site is positioned in the middle of the 5′-proximal half “seed” region critical for the hybridization of miRNAs to targets. We provide evidence that the edited miR-376 RNA silences specifically a different set of genes. Repression of phosphoribosyl pyrophosphate synthetase 1, a target of the edited miR-376 RNA and an enzyme involved in the uric-acid synthesis pathway, contributes to tight and tissue-specific regulation of uric-acid levels, revealing a previously unknown role for RNA editing in miRNA-mediated gene silencing.