[21] More recent studies have characterized other key components of the m6A methyltransferase complex in mammals, including METTL14,[22][23] Wilms tumor 1 associated protein (WTAP),[22][24] VIRMA[25] and METTL5.

[26] Following a 2010 speculation of m6A in mRNA being dynamic and reversible,[27] the discovery of the first m6A demethylase, fat mass and obesity-associated protein (FTO) in 2011[28] confirmed this hypothesis and revitalized the interests in the study of m6A.

[36] In budding yeast (Saccharomyces cerevisiae), the expression of the homologue of METTL3, IME4, is induced in diploid cells in response to nitrogen and fermentable carbon source starvation and is required for mRNA methylation and the initiation of correct meiosis and sporulation.

A >90% reduction of m6A levels in mature plants leads to dramatically altered growth patterns and floral homeotic abnormalities.

[16] By integrating all m6A sequencing data, a novel database called RMBase has identified and provided ~200,000 sites in the human and mouse genomes corresponding to N6-Methyladenosines (m6A) in RNA.

[39] The study combining m6A-CLIP with rigorous cell fractionation biochemistry reveals that m6A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover.

Analysis of m6A in mouse brain RNA reveals that m6A levels are low during embryonic development and increase dramatically by adulthood.

[16] In mESCs and during mouse development, FTO has been shown to mediated LINE1 RNA m6A demethylation and consequently affect local chromatin state and nearby gene transcription.

[42] Additionally, silencing the m6A methyltransferase significantly affects gene expression and alternative RNA splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis.

[47] Considering the versatile functions of m6A in various physiological processes, it is thus not surprising to find links between m6A and numerous human diseases; many originated from mutations or single nucleotide polymorphisms (SNPs) of cognate factors of m6A.

SNPs of FTO have been shown to associate with body mass index in human populations and occurrence of obesity and diabetes.

[75][76][77][78][79][80] These results suggest m6A and its cognate factors play crucial roles in regulating virus life cycles and host-viral interactions.

[80] M6A methylation is also widespread in bacteria, influencing functions such as DNA replication, repair, and gene expression, and prokaryotic defense.

In replication, M6A modifications mark DNA regions where the initiation stage takes place as well as regulates precise timing via the Dam methyltransferase in E.

In the reproductive system, m6A modifications have been shown to disrupt the maternal-to-zygotic mRNA transition and negatively affect both gamete formation and fertility.