<i>N</i>6‐methyladenosine modification in <scp>mRNA</scp>: machinery, function and implications for health and diseases

Maity, Arpita; Das, Biswadip

doi:10.1111/febs.13614

Cited by 181 publications

(183 citation statements)

References 147 publications

(339 reference statements)

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“…The m6A methylation is formed during nascent pre‐mRNA processing by a methyltransferase complex consisting of METTL3, METTL14 and WTAP and removed by FTO and ALKBH5 37, 38, 39, 40, 41. This modification plays important roles in neuronal disorders, immune response, obesity and cancer 42. The m6A modification is implicated in neurodegeneration and its associated disorders, for example Parkinson's disease 43.…”

Section: Discussionmentioning

confidence: 99%

METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide‐induced inflammatory response in human dental pulp cells

Feng

Meng

et al. 2018

J Cellular Molecular Medi

166

148

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Dental pulp inflammation is a widespread public health problem caused by oral bacterial infections and can progress to pulp necrosis and periapical diseases. N6‐methyladenosine (m6A) is a prevalent epitranscriptomic modification in mRNA. Previous studies have demonstrated that m6A methylation plays important roles in cell differentiation, embryonic development and stress responses. However, whether m6A modification affects dental pulp inflammation remains unknown. To address this issue, we investigated the expression of m6A and N6‐adenosine methyltransferase (METTL3, METTL14) as well as demethylases (FTO, ALKBH5) and found that the levels of m6A and METTL3 were up‐regulated in human dental pulp cells (HDPCs) stimulated by lipopolysaccharide (LPS). Furthermore, we knocked down METTL3 and demonstrated that METTL3 depletion decreased the expression of inflammatory cytokines and the phosphorylation of IKKα/β, p65 and IκBα in the NF‐κB signalling pathway as well as p38, ERK and JNK in the MAPK signalling pathway in LPS‐induced HDPCs. The RNA sequencing analysis revealed that the vast number of genes affected by METTL3 depletion was associated with the inflammatory response. Previous research has shown that METTL3‐dependent N6‐adenosine methylation plays an important role in mRNA splicing. In this study, we found that METTL3 knockdown facilitated the expression of MyD88S, a splice variant of MyD88 that inhibits inflammatory cytokine production, suggesting that METTL3 might inhibit the LPS‐induced inflammatory response of HDPCs by regulating alternative splicing of MyD88. These data shed light on new findings in epitranscriptomic regulation of the inflammatory response and open new avenues for research into the molecular mechanisms of dental pulp inflammation.

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Section: Discussionmentioning

confidence: 99%

METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide‐induced inflammatory response in human dental pulp cells

Feng

Meng

et al. 2018

J Cellular Molecular Medi

166

148

View full text Add to dashboard Cite

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“…The mammalian m6A modification system has at least three key components (Box 1): the writers (i.e., the methyltransferases), the erasers (i.e., the demethylases), and the readers (i.e., effector proteins that directly bind m6A) [15, 17, 18]. Studies of the m6A readers reveal an interesting link between m6A modification and mRNA turnover rate.…”

Section: Epitranscriptomics Of M6amentioning

confidence: 99%

“…The dynamics of reversible m6A modification in mRNAs are controlled by a system with at least three components: i) the “writers”, including the METTL3 and METTL14 methyltransferases, and at least one co-factor, WTAP; ii) the “erasers”, including the FTO and ALKBH5 demethylases; and iii) the “readers", effectors which include at least five proteins (YTHDF1–3 and YTHDC1–2) that are believed to directly interact with m6A [15, 17, 18]. The balance between activities of the writers and the erasers determines a transcriptome's extent of m6A modification, which, together with the m6A readers, influences the function and fate of m6A-modified mRNAs.…”

Section: Figurementioning

confidence: 99%

Emerging Themes in Regulation of Global mRNA Turnover in cis

Chen

Shyu

2017

Trends in Biochemical Sciences

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Messenger RNA (mRNA) is the molecule that conveys genetic information from DNA to the translation apparatus. mRNAs in all organisms display a wide range of stability, and mechanisms have evolved to selectively and differentially regulate individual mRNA stability in response to intra-cellular and extra-cellular cues. In recent years, three seemingly distinct aspects of RNA biology—mRNA N6-methyladenosine (m6A) modification, alternative 3’ end processing and polyadenylation (APA), and mRNA codon usage—have been linked to mRNA turnover, and all three aspects function to regulate global mRNA stability in cis. Here, we discuss the discovery and molecular dissection of these mechanisms in relation to how they impact the intrinsic decay rate of mRNA in eukaryotes, leading to transcriptome reprogramming.

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“…In addition, changes in m 6 A modification are observed to be involved in multiple cellular processes, which may have impacts on several human diseases 7, 8. Recently developed methods have enabled researchers to determine the precise location and abundance of m 6 A residues and their implication in human diseases, especially in cancers 7, 9. Herein, we provide an updated review regarding the critical regulatory effects of m 6 A modification in several human cancers, and to improve the understanding of mechanisms of tumour carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2018

J Cellular Molecular Medi

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As the most abundant and reversible RNA modification in eukaryotic cells, m6A triggers a new layer of epi‐transcription. M6A modification occurs through a methylation process modified by “writers” complexes, reversed by “erasers”, and exerts its role depending on various “readers”. Emerging evidence shows that there is a strong association between m6A and human diseases, especially cancers. Herein, we review bi‐aspects of m6A in regulating cancers mediated by the m6A‐associated proteins, which exert vital and specific roles in the development of various cancers. Generally, the m6A modification performs promotion or inhibition functions (dual role) in tumorigenesis and progression of various cancers, which suggests a new concept in cancer regulations. In addition, m6A‐targeted therapies including competitive antagonists of m6A‐associated proteins may provide a new tumour intervention in the future.

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N6‐methyladenosine modification in mRNA: machinery, function and implications for health and diseases

Cited by 181 publications

References 147 publications

METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide‐induced inflammatory response in human dental pulp cells

METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide‐induced inflammatory response in human dental pulp cells

Emerging Themes in Regulation of Global mRNA Turnover in cis

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

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