Gene expression regulation mediated through reversible m6A RNA methylation

Abstract

Cellular RNAs carry diverse chemical modifications that used to be regarded as static and having minor roles in 'fine-tuning' structural and functional properties of RNAs. In this Review, we focus on reversible methylation through the most prevalent mammalian mRNA internal modification, N(6)-methyladenosine (m(6)A). Recent studies have discovered protein 'writers', 'erasers' and 'readers' of this RNA chemical mark, as well as its dynamic deposition on mRNA and other types of nuclear RNA. These findings strongly indicate dynamic regulatory roles that are analogous to the well-known reversible epigenetic modifications of DNA and histone proteins. This reversible RNA methylation adds a new dimension to the developing picture of post-transcriptional regulation of gene expression.

Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification

“…METTL14 representatives often show disruptions of their active site motifs suggesting that they are inactive versions (Supporting Information). METTL3 and METTL14 cognates are typically subunits of a dimeric enzyme, catalyzing N 6 A methylation of specific positions in mRNAs 67, 68. Consistent with this, in METTL3 the MTase is fused to N‐terminal ssRNA‐binding CCCH domains (Fig.…”

“…It was also predicted then that certain members of the AlkB family were likely to demethylate m 6 A in RNA 96. Subsequently, such demethylation of m 6 A in RNA was indeed observed to be the mechanism for resetting methyl marks generated by N 6 A RNA MTases 68, 99. Oxidation of the methyl group by these enzymes results in formation of N 6 hmA and N 6 fA, which restore the original base, releasing formaldehyde and formate 100.…”

“…These include the SAD/SRA, which recognizes 5mC in DNA; EVE, which binds DNA with 5hmC; and the PUA, which binds modified RNA (including the YTH family which binds m 6 A containing RNA) 20, 68, 111, 112, 113, 114, 115. Another family displaying this fold, the ASCH domain, was predicted to bind several modified bases, and is found fused to or operonically associated with the N 6 A‐MTase domain on multiple occasions in bacteria 15, 112 (Fig.…”

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

“…Alpha‐ketoglutarate‐dependent dioxygenase homolog 5 (ALKBH5), the second RNA demethylase, was first reported in 2013 12. Both FTO and ALKBH5 belong to the alpha‐ketoglutarate‐dependent dioxygenase family and catalyse m 6 A demethylation in a Fe(II)‐ and alpha‐ketoglutarate‐dependent manner 13, 14. Analogous to ALKBH5, alpha‐ketoglutarate‐dependent dioxygenase homolog 3 (ALKBH3) has been demonstrated demethylase activity for 1‐methyladenine and 3‐methylcytosine 15.…”

Epigenetics: from the past to the present

“…Such modifications also have 'writers' (methyltransferases METTL3, METTL14) and 'readers' (YTHDF2, hnRNPs), and they are thought to be important in many aspects of human biology (Liu & Pan 2015). ALKBH5 is another recently reported demethylase of m 6 A which participates in mRNA export and metabolism (Zheng et al 2013;Fu et al 2014). Although there are several RNA modifications that have been known for many years (more than 100), few studies have examined their biological functions or the possibility that they are part of an 'RNA epigenetics' (Liu & Jia 2014).…”