Seminars

MicroRNAs (miRNAs) are post-transcriptional regulators that silence hundreds of target transcripts through base-pairing to their seed regions (positions 2-8), thereby controlling diverse pathophysiology. High-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP, also called CLIP-Seq) has been used to map global RNA–protein interactions, also applying to Argonaute (AGO CLIP) to identify miRNA target transcriptome. By analyzing AGO CLIP, we have discovered that redirection of miRNA-target interactions has prevailed in cardiac hypertrophy via redox-mediated RNA modification, 8-oxoguanine (o⁸G). We specifically sequenced oxidized miRNAs in a rat model of the redox-associated condition cardiac hypertrophy. We found that position-specific o⁸G modifications are generated in seed regions (positions 2–8) of selective miRNAs, and function to regulate other mRNAs through o⁸G•A base pairing. o⁸G is induced predominantly at position 7 of miR-1 (7o⁸G-miR-1) by treatment with an adrenergic agonist. Introducing 7o⁸G-miR-1 or 7U-miR-1 (in which G at position 7 is substituted with U) alone is sufficient to cause cardiac hypertrophy in mice, and the mRNA targets of o⁸G-miR-1 function in affected phenotypes; the specific inhibition of 7o⁸G-miR-1 in mouse cardiomyocytes was found to attenuate cardiac hypertrophy. Recently, we also found that o⁸G-miRNAs are widespread in various cancer patients to control tumorigenesis. Our findings show that the position-specific oxidation of miRNAs could serve as an epitranscriptional mechanism to coordinate pathophysiological redox-mediated gene expression in diseases.