Abstract

Summary N 6 -methyladenosine (m 6 A) 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 m 6 A-positive and m 6 A-negative RNA populations. Both the presence and extent of A-to-I sites in m 6 A-negative RNA transcripts suggest a negative correlation between m 6 A and A-to-I. Suppression of m 6 A-catalyzing enzymes results in global A-to-I RNA editing changes. Further depletion of m 6 A modification increases the association of m 6 A-depleted transcripts with adenosine deaminase acting on RNA (ADAR) enzymes, resulting in upregulated A-to-I editing on the same m 6 A-depleted transcripts. Collectively, the effect of m 6 A on A-to-I suggests a previously underappreciated interplay between two distinct and abundant RNA modifications, highlighting a complex epitranscriptomic landscape.