Dynamic m(6)A modification and its emerging regulatory role in mRNA splicing

Recent studies on enzymes regulating dynamic N-6-methyl-adenosine (m(6)A) in RNA together with the findings from m(6)A-methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq/m(6) A-seq) have revealed a broad biological role of m(6)A in RNA processing, development, differentiation, metabolism and fertility. RNA m(6)A 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 m(6)A demethylases, catalyze m(6)A removal. Five m(6)A-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 m(6)A results in altered expression of thousands of genes and affects mRNA stability and splicing at the cellular level. Here, we summarize recent discoveries about m(6)A methyltransferases (writers), demethylases (erasers) and binding proteins (readers), and further discuss the potential impacts of m(6)A on RNA processing, especially on mRNA splicing.