Trends in Genetics
Volume 36, Issue 1, January 2020, Pages 44-52
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Review
The Biogenesis and Precise Control of RNA m6A Methylation

https://doi.org/10.1016/j.tig.2019.10.011Get rights and content

Highlights

  • m6A is an abundant and conserved RNA modification in eukaryotic RNAs that affects RNA fate and is characterized by preferential deposition within the RRACH motif and enrichment in mRNA coding sequences and 3′-untranslated regions.

  • The RNA methyltransferase complex, comprising of the methyltransferase-like 3 (METTL3)/METTL14 (methyltransferase-like 14) core subunit and other cofactors, is responsible for the deposition of m6A on mRNA, where METTL3 is the catalytic subunit and METTL14 is crucial for target recognition.

  • Trimethylation of histone H3 at Lys36 emerges as a general determinant for m6A deposition by recruiting METTL14 and the associated RNA methyltransferase complex to guide m6A deposition cotranscriptionally.

  • By recruiting or sequestering m6A methyltransferase components, transcription factors exhibit new roles in controlling m6A levels on specific transcripts in specific cellular contexts.

N6-Methyladenosine (m6A) is the most prevalent internal RNA modification in mRNA, and has been found to be highly conserved and hard-coded in mammals and other eukaryotic species. The importance of m6A for gene expression regulation and cell fate decisions has been well acknowledged in the past few years. However, it was only until recently that the mechanisms underlying the biogenesis and specificity of m6A modification in cells were uncovered. We review up-to-date knowledge on the biogenesis of the RNA m6A modification, including the cis-regulatory elements and trans-acting factors that determine general de novo m6A deposition and modulate cell type-specific m6A patterns, and we discuss the biological significance of such regulation.

Section snippets

The Landmarks of the m6A Epitranscriptome

Similarly to DNA and protein, the chemical structure of RNA can be modified in cells to serve as an epigenetic mechanism of gene expression control [1]. To date >170 types of RNA modification have been identified [2, 3, 4], including those in mRNA, tRNA, rRNA, small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), and long noncoding RNA (lncRNA). A global landscape of any type of RNA modification was recently described with the advent of next-generation sequencing (NGS) methods that delineate

RNA m6A Machinery: From Writing to Interpreting

m6A methylation is introduced into mRNAs by a multicomponent m6A methyltransferase complex (MTC, also known as m6A ‘writer’; Figure 1). The core component of MTC is a ∼200 kDa heterodimer composed of methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14) [19,20]. Both METTL3 and METTL14 contain methyltransferase domains; however, structural studies revealed that METTL3 is the only catalytically active subunit and requires bound donor substrate S-adenosyl-methionine (SAM) in

Evidence for Cotranscriptional m6A Deposition

Transcription is the first step of gene expression in which the genetic information is transferred from DNA to RNA by the enzyme RNA polymerase (RNA pol). Before separation from the DNA template and RNA pol, the nascent transcripts (known as nascent RNAs or chromatin-associated RNAs), a class of unstable RNAs of heterogeneous size, undergo a series of processing events such as 5′ capping, 3′ polyadenylation, and splicing. In 1976 it was found that m6A is present in pre-mRNA-containing

Histone Modification Guides m6A Deposition in CDS and 3′-UTRs

The unique pattern of the m6A epitranscriptome indicates that there could be a general but delicated mechanism for the precise deposition of m6A in cellulo. Strikingly, it was found that histone H3 lysine 36 trimethylation (H3K36me3), that is classically associated with active transcription and is deposited cotranscriptionally, shows a similar CDS and 3′ UTR distribution pattern to m6A, indicating an unappreciated link between H3K36me3 and m6A RNA modification [27]. Further analysis of the m6A

H3K36me3–m6A Crosstalk in Mouse Embryonic Stem Cell (mESC) Pluripotency

The aforementioned data link the epigenome with the epitranscriptome and add an additional complexity to the gene expression network. In fact, it was shown that a decrease in H3K36me3 suppressed global gene expression, likely through an m6A-mediated influence on mRNA stability [27]. H3K36me3 is most commonly associated with transcription of active euchromatin, and has been implicated in diverse cellular processes including alternative splicing, DNA repair, and recombination [73,74]. Given the

Transcription Factors Modulate Cell Context-Specific m6A Methylation

Similarly to the epigenome, the epitranscriptome is highly plastic and reacts to changing external conditions [76,77], thus allowing dynamic gene expression regulation. Beyond the general regulation of the m6A epitranscriptome by H3K36me3, dynamic regulation of m6A could be achieved by transcription factor-mediated recruitment of m6A MTC to specific chromatin loci in specific cell contexts (Figure 2).

ZFP217, a chromatin-associated zinc-finger protein that plays a role in maintaining

Concluding Remarks and Future Perspectives

Inspired by the discovery of histone and DNA demethylases, RNA methylation was shown to be reversible as early as 2008 when FTO was reported to be the demethylase of m3U [48]. m6A was later found to be the dominant substrate of FTO in the nucleus that undergoes reversible regulation in cellulo [46]. The biological significance of RNA modifications, especially of m6A, has been well acknowledged in various physiological and pathological processes [1,80, 81, 82, 83, 84]. However, how de novo m6A

Acknowledgments

This work was supported in part by the National Institutes of Health (NIH) grants R01 CA214965, R01 CA236399, R01 CA211614, and R56 DK120282 to J.C. J.C. is a Leukemia and Lymphoma Society (LLS) Scholar. We apologize to colleagues whose work could not be cited owing to space constraints.

Disclaimer Statement

J.C. is the scientific founder of Genovel Biotech Corporation.

Glossary

S-Adenosyl-methionine (SAM)
an important methyl donor derived from ATP and methionine via the one-carbon metabolism. SAM is the main methyl donor in cellular methylation reactions, including DNA methylation, RNA methylation, and histone methylation.
Crosslinking and immunoprecipitation (CLIP)
an antibody-based technique developed for studying RNA–protein interactions. Instead of using formaldehyde that is commonly used for DNA–protein crosslinking, CLIP uses UV light and the crosslinking is

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