The importance of physiological and disease contexts in capturing mRNA modifications

The variety of modifications decorating various RNA species has prompted researchers to study messenger RNA (mRNA) modifications that are likely to have, like N⁶-methyladenosine (m⁶A), important biological functions. Yet tackling these modifications has proved more complicated than anticipated. In this Perspective, we discuss two major obstacles to progress in epitranscriptomic research: the low abundance of most mRNA modification and the nonspecificity of many mRNA modifiers. We then shift our focus to the removal of mRNA modifications and their upstream regulation, emphasizing the context-dependent nature of epitranscriptomic regulation. We illustrate how specific modifications, such as N¹-methyladenosine (m¹A) and pseudouridine, are enriched in distinct environments, most notably within mitochondria and in certain physiopathological conditions. By focusing on biological settings in which non-m⁶A modifications are more abundant, we could deepen our understanding of their precise roles in gene regulation.