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

• Published in: RNA (Cambridge) 2018-03, Vol.24 (3), p.262-267
• Main Authors: Darnell, Robert B, Ke, Shengdong, Darnell, James E
• Format: Article
• Language: English
• Subjects: Divergent Views
• ISSN: 1355-8382; 1469-9001
• DOI: 10.1261/rna.065219.117

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 (>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.