m 6 A in mRNA: An Ancient Mechanism for Fine-Tuning Gene Expression

Abstract

Modifications in mRNA constitute ancient mechanisms to regulate gene expression post-transcriptionally. N-methyladenosine (mA) is the most prominent mRNA modification, and is installed by a large methyltransferase complex (the mA 'writer'), not only specifically bound by RNA-binding proteins (the mA 'readers'), but also removed by demethylases (the mA 'erasers'). mA mRNA modifications have been linked to regulation at multiple steps in mRNA processing. In analogy to the regulation of gene expression by miRNAs, we propose that the main function of mA is post-transcriptional fine-tuning of gene expression. In contrast to miRNA regulation, which mostly reduces gene expression, we argue that mA provides a fast mean to post-transcriptionally maximize gene expression. Additionally, mA appears to have a second function during developmental transitions by targeting mA-marked transcripts for degradation.

Epitranscriptomic profiling in human placenta: N6‐methyladenosine modification at the 5′‐untranslated region is related to fetal growth and preeclampsia

“…18 However, WTAP-independent methylation sites only exist at the 5′-UTR, and such methylations are reported to have a positive correlation with translation efficiency. The m 6 A modification mechanism at the 5′-UTR is different from that at the vicinity of the stop codon.…”

“…6,7 Sequences containing m 6 A are usually located in the vicinity of a stop codon, especially within the 3′-UTR, and they have a consensus sequence of RRACHR, where R is a purine and H is any base except for G. 6,7 m 6 A modifications are involved in post-transcriptional regulation, especially in determining the stability and lifespan of mRNA. 18 Notably, although the levels of mRNA (arising from gene expression) and protein are positively correlated, the correlation is weak, that is, it is not a perfect correlation. [10][11][12][13][14][15] The site of m 6 A in mRNA differs with cell and tissue types; moreover, m 6 A levels change in response to external stimuli, 16,17 thereby functioning as a dynamic type of modification that fine-tunes gene expression.…”

Iron homeostasis regulates facultative heterochromatin assembly in adaptive genome control

“…9). Indeed, RNA modifying enzymes containing iron-sulfur clusters and radical SAM domains catalyze a variety of RNA modifications that affect RNA stability or function 56,57 . Determining whether Clr4 recruitment may be facilitated through iron-dependent RNA modification activities will be an important topic for future studies.…”

Role of RNA modifications in brain and behavior

“…19 m 5 C is mainly found in UTRs of mRNA and near binding sites for Argonaute, part of the RNA degradation machinery. 20,21 Similar to m 6 A, m 5 C modification is also dynamic, but unlike m 6 A, m 5 C is not removed but is oxidized to 5-hydroxymethylcytidine (hm 5 C). 22–25 hm 5 C tends to be found in polyribosomes and is associated with increased translation efficiency in Drosophila.…”

“…20 The m 6 A base is recognized by RNA-binding protein readers or may be erased by demethylase or by RNA turnover. Methylation of adenosine in mRNAs is catalyzed by a methyltransferase complex containing METTL3 (also called MT-A70, MTA and IME4) in cooperation with METTL14.…”