N6-Methyladenosines Modulate A-to-I RNA Editing

Abstract

N⁶-methyladenosine (m⁶A) and adenosine-to-inosine (A-to-I) editing are two of the most abundant RNA modifications, both at adenosines. Yet, the interaction of these two types of adenosine modifications is largely unknown. Here we show a global A-to-I difference between m⁶A-positive and m⁶A-negative RNA populations. Both the presence and extent of A-to-I sites in m⁶A-negative RNA transcripts suggest a negative correlation between m⁶A and A-to-I. Suppression of m⁶A-catalyzing enzymes results in global A-to-I RNA editing changes. Further depletion of m⁶A modification increases the association of m⁶A-depleted transcripts with adenosine deaminase acting on RNA (ADAR) enzymes, resulting in upregulated A-to-I editing on the same m⁶A-depleted transcripts. Collectively, the effect of m⁶A on A-to-I suggests a previously underappreciated interplay between two distinct and abundant RNA modifications, highlighting a complex epitranscriptomic landscape.

Keywords: A-to-I; ADAR; Alu; N(6)-methyladenosines; RNA editing; RNA modification; RNA structure; m(6)A; m(6)A enzymes.