Pre-mRNA processing includes N6 methylation of adenosine residues that are retained in mRNA exons and the fallacy of “RNA epigenetics”
- 1Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York 10065, USA
- 2Laboratory of Molecular Cell Biology, The Rockefeller University, New York, New York 10065, USA
- Corresponding author: darnell{at}mail.rockefeller.edu
Abstract
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 (m6A) 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 m6A content in HeLa cell mRNA, suggesting that specification of mRNA stability may be the major role of m6A 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 m6A in mRNA, suggesting no common obligatory role of m6A 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.
Footnotes
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Article is online at http://www.rnajournal.org/cgi/doi/10.1261/rna.065219.117.
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Freely available online through the RNA Open Access option.
This article, published in RNA, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
