Position-specific oxidation of miR-1 encodes cardiac hypertrophy

Abstract

The 8-oxoguanine modification of the microRNA miR-1 results in redirected recognition and silencing of target genes and leads to cardiac hypertrophy in mice. In pathophysiology, reactive oxygen species oxidize biomolecules that contribute to disease phenotypes(1). One such modification, 8-oxoguanine(2)(o(8)G), is abundant in RNA(3)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 hypertrophy(4). We find that position-specific o(8)G modifications are generated in seed regions (positions 2-8) of selective miRNAs, and function to regulate other mRNAs through o(8)G center dot A base pairing. o(8)G is induced predominantly at position 7 of miR-1 (7o(8)G-miR-1) by treatment with an adrenergic agonist. Introducing 7o(8)G-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 o(8)G-miR-1 function in affected phenotypes; the specific inhibition of 7o(8)G-miR-1 in mouse cardiomyocytes was found to attenuate cardiac hypertrophy. o(8)G-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.