Methylation Modifications in Eukaryotic Messenger RNA

RNA methylation modifications have been found for decades of years, which occur at different RNA types of numerous species, and their distribution is species-specific. However, people rarely know their biological functions. There are several identified methylation modifications in eukaryotic messenger RNA (mRNA), such as N-7-methylguanosine (m(7)G) at the cap, N-6-methyl-2'-O-methyladenosine (m(6)A(m)), 2'-O-methylation (N-m) within the cap and the internal positions, and internal N-6-methyladenosine (m(6)A) and 5-methylcytosine (m(5)C). Among them, m(7)G cap was studied more clearly and found to have vital roles in several important mRNA processes like mRNA translation, stability and nuclear export. m(6)A as the most abundant modification in mRNA was found in the 1970s and has been proposed to function in mRNA splicing, translation, stability, transport and so on. m(6)A has been discovered as the first RNA reversible modification which is demethylated directly by human fat mass and obesity associated protein (FTO) and its homolog protein, alkylation repair homolog 5 (ALKBH5). FTO has a special demethylation mechanism that demethylases m(6)A to A through two over-oxidative intermediate states: N-6-hydroxymethyladenosine (hm(6)A) and N-6-formyladenosine (f(6)A). The two newly discovered m(6)A demethylases, FTO and ALKBH5, significantly control energy homeostasis and spermatogenesis, respectively, indicating that the dynamic and reversible m(6)A, analogous to DNA and histone modifications, plays broad roles in biological kingdoms and brings us an emerging field "RNA Epigenetics". 5-methylcytosine (5mC) as an epigenetic mark in DNA has been studied widely, but m(5)C in mRNA is seldom explored. The bisulfide sequencing showed m(5)C is another abundant modification in mRNA, suggesting that it might be another RNA epigenetic mark. This review focuses on the main methylation modifications in mRNA to describe their formation, distribution, function and demethylation from the current knowledge and to provide future perspectives on functional studies.