N~6 -methyl-adenosine (m ~6A) in RNA: An Old Modification with A Novel Epigenetic Function

N⁶-methyl-adenosine (m⁶A) is one of the most common and abundant modifications on RNA molecules present in eukaryotes. However, the biological significance of m⁶A methylation remains largely unknown. Several independent lines of evidence suggest that the dynamic regulation of m⁶A may have a profound impact on gene expression regulation. The m⁶A modification is catalyzed by an unidentified methyltransferase complex containing at least one subunit methyltransferase like 3 (METTL3). m⁶A modification on messenger RNAs (mRNAs) mainly occurs in the exonic regions and 3′-untranslated region (3′-UTR) as revealed by high-throughput m⁶A-seq. One significant advance in m⁶A research is the recent discovery of the first two m⁶A RNA demethylases fat mass and obesity-associated (FTO) gene and ALKBH5, which catalyze m⁶A demethylation in an α-ketoglutarate (α-KG)- and Fe²⁺-dependent manner. Recent studies in model organisms demonstrate that METTL3, FTO and ALKBH5 play important roles in many biological processes, ranging from development and metabolism to fertility. Moreover, perturbation of activities of these enzymes leads to the disturbed expression of thousands of genes at the cellular level, implicating a regulatory role of m⁶A in RNA metabolism. Given the vital roles of DNA and histone methylations in epigenetic regulation of basic life processes in mammals, the dynamic and reversible chemical m⁶A modification on RNA may also serve as a novel epigenetic marker of profound biological significances.