Dynamic m6A modification and its emerging regulatory role in mRNA splicing

Abstract

Recent studies on enzymes regulating dynamic N6-methyl-adenosine (m6A) in RNA together with the findings from m6A-methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq/m6As-seq) have revealed a broad biological role of m6A in RNA processing, development, differentiation, metabolism and fertility. RNA m6A methylation is catalyzed by a multicomponent methyltransferase complex composed of at least three subunits: METTL3, METTL14 and Wilms tumor 1-associated protein (WTAP), in which METTL3 and METTL14 serve as catalytic subunits, while WTAP as regulatory subunit. Dioxygenases FTO and ALKBH5, as the first two known m6A demethylases, catalyze m6A removal. Five m6A-binding proteins are classified into cytoplasmic YT521-B homology (YTH) domain-containing family YTHDF1–3 and nuclear YTHDC1–2. Perturbation of enzymatic activities catalyzing dynamic m6A results in altered expression of thousands of genes and affects mRNA stability and splicing at the cellular level. Here, we summarize recent discoveries about m6A methyltransferases (writers), demethylases (erasers) and binding proteins (readers), and further discuss the potential impacts of m6A on RNA processing, especially on mRNA splicing.