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By using a cell fraction technique that separates chromatin-associated nascent RNA, newly completed nucleoplasmic mRNA and cytoplasmic mRNA, we have shown in a previous study that residues in exons are methylated (m 6 A) in nascent pre-mRNA and remain methylated in the same exonic residues in nucleoplasmic and cytoplasmic mRNA. Thus, there is no evidence of a substantial degree of demethylation in mRNA exons that would correspond to so-called “epigenetic” demethylation. The turnover rate of mRNA molecules is faster, depending on m 6 A content in HeLa cell mRNA, suggesting that specification of mRNA stability may be the major role of m 6 A exon modification. In mouse embryonic stem cells (mESCs) lacking Mettl3, the major mRNA methylase, the cells continue to grow, making the same mRNAs with unchanged splicing profiles in the absence (&gt;90%) of m 6 A in mRNA, suggesting no common obligatory role of m 6 A in splicing. All these data argue strongly against a commonly used “reversible dynamic methylation/demethylation” of mRNA, calling into question the concept of “RNA epigenetics” that parallels the well-established role of dynamic DNA epigenetics.

Pre-mRNA processing includes <i>N</i><sup>6</sup> methylation of adenosine residues that are retained in mRNA exons and the fallacy of “RNA epigenetics”

Pre-mRNA processing includes N6 methylation of adenosine residues that are retained in mRNA exons and the fallacy of “RNA epigenetics”

Pre-mRNA processing includes N⁶ methylation of adenosine residues that are retained in mRNA exons and the fallacy of “RNA epigenetics”