Position-specific oxidation of miR-1 encodes cardiac hypertrophy

In pathophysiology, reactive oxygen species oxidize biomolecules that contribute to disease phenotypes¹. One such modification, 8-oxoguanine² (o⁸G), is abundant in RNA³ but its epitranscriptional role has not been investigated for microRNAs (miRNAs). Here we specifically sequence oxidized miRNAs in a rat model of the redox-associated condition cardiac hypertrophy⁴. We find 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. o⁸G-miR-1 is also implicated in patients with cardiomyopathy. Our findings show that the position-specific oxidation of miRNAs could serve as an epitranscriptional mechanism to coordinate pathophysiological redox-mediated gene expression.