Rethinking m<sup>6</sup>A Readers, Writers, and Erasers

Meyer, Kate D.; Jaffrey, Samie R.

doi:10.1146/annurev-cellbio-100616-060758

Cited by 857 publications

(910 citation statements)

References 99 publications

(232 reference statements)

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“…With the advance of research, the panel of genes reported to be involved in m6A regulation was in rapid expansion . Considering the roles of other emerging genes in modulating m6A has not been well characterized yet, only the seven canonical regulators (METTL3, METTL14, YTHDF1, YTHDF2, YTHDF3, ALKBH5, FTO) were included in our study.…”

Section: Discussionmentioning

confidence: 99%

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

et al. 2019

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Background As the most abundant epigenetic modification on mRNAs and long non‐coding RNAs, N6‐methyladenosine (m6A) modification extensively exists in mammalian cells. Controlled by writers (methyltransferases), readers (signal transducers), and erasers (demethylases), m6A influences mRNA structure, maturation, and stability, thus negatively regulating protein expression in a post‐translational manner. Nevertheless, current understanding of m6A's roles in tumorigenesis, especially in gastric cancer (GC) remains to be unveiled. In this study, we assessed m6A's clinicopathological relevance to GC and explored the underlying mechanisms. Methods By referring to a proteomics‐based GC cohort we previously generated and the TCGA‐GC cohort, we merged expressions of canonical m6A writers (METTL3/METTL14), readers (YTHDF1/YTHDF2/YTHDF3), and erasers (ALKBH5/FTO), respectively, as W, R, and E signatures to represent m6A modification. We stratified patients according to these signatures to decipher m6A's associations with crucial mutations, prognosis, and clinical indexes. m6A's biological functions in GC were predicted by gene set enrichment analysis (GSEA) and validated by in vitro experiments. Results We discovered that W and R were potential tumor suppressive signatures, while E was a potential oncogenic signature in GC. According to W/R/E stratifications, patients with low m6A‐indications were accompanied with higher mutations of specific genes ( CDH1 , AR , GLI3 , SETBP1 , RHOA , MUC6 , and TP53 ) and also demonstrated adverse clinical outcomes. GSEA suggested that reduced m6A was correlated with oncogenic signaling and phenotypes. Through in vitro experiments, we proved that m6A suppression (represented by METTL14 knockdown) promoted GC cell proliferation and invasiveness through activating Wnt and PI3K‐Akt signaling, while m6A elevation (represented by FTO knockdown) reversed these phenotypical and molecular changes. m6A may also be involved in interferon signaling and immune responses of GC. Conclusions Our work demonstrated that low‐m6A signatures predicted adverse clinicopathological features of GC, while the reduction of RNA m6A methylation activated oncogenic Wnt/PI3K‐Akt signaling and promoted malignant phenotypes of GC cells.

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Section: Discussionmentioning

confidence: 99%

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

et al. 2019

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“…Systematic profiling and characterization have revealed conservation across different kingdoms and diverse cellular functions of m 6 A/m modifications on mRNA 42 . m 6 A has been found on HSV-1 mRNA for decades but the transcript and position containing the modification as well as the underlying function remain unclear 43 .…”

Section: Discussionmentioning

confidence: 99%

Viral and cellular N6-methyladenosine and N6,2′-O-dimethyladenosine epitranscriptomes in the KSHV life cycle

et al. 2017

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N 6-methyladenosine (m6A) and N6, 2′-O-Dimethyladenosine (m6Am) modifications (m6A/m) of messenger RNA mediate diverse cellular functions. Oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) has latent and lytic replication phases that are essential for the development of KSHV-associated cancers. To date, the role of m6A/m in KSHV replication and tumorigenesis is unclear. Here, we provide mechanistic insights by examining the viral and cellular m6A/m epitranscriptomes during KSHV latent and lytic infection. KSHV transcripts contain abundant m6A/m modifications during latent and lytic replication, and these modifications are highly conserved among different cell types and infection systems. Knockdown of YTHDF2 enhanced lytic replication by impeding KSHV RNA degradation. YTHDF2 binds to viral transcripts and differentially mediates their stability. KSHV latent infection induces 5′UTR hypomethylation and 3′UTR hypermethylation of the cellular epitranscriptome, regulating oncogenic and epithelial-mesenchymal transition pathways. KSHV lytic replication induces dynamic reprograming of epitranscriptome, regulating pathways that control lytic replication. These results reveal a critical role of m6A/m modifications in KSHV lifecycle and provide rich resources for future investigations.

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“…In addition to these findings, numerous studies of m 6 A in diverse physiological contexts failed to find that FTO knockdown shows an opposite effect of METTL3 knockdown [54]. FTO knockdown should show the opposite effect as METTL3 knockdown if FTO removes m 6 A.…”

Section: Inconsistencies With M 6 a As The Substrate Of Ftomentioning

confidence: 99%

FTO, m⁶A_m, and the hypothesis of reversible epitranscriptomic mRNA modifications

2018

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The fate of mRNA is regulated by epitranscriptomic nucleotide modifications, the most abundant of which is N -methyladenosine (m A). Although the pattern and distribution of m A in mRNA is mediated by specific methyltransferases, a recent hypothesis is that specific demethylases or 'erasers' allow m A to be dynamically reversed by signaling pathways. In this Review, we discuss the data in support and against this model. New insights into the function of fat mass and obesity-associated protein (FTO), the original enzyme thought to be an m A eraser, reveal that its physiologic target is not m A, but instead is N ,2'-O-dimethyladenosine (m A ). Another m A demethylase, ALKBH5, appears to have functions limited to sperm development in normal mice. Overall, the majority of the data suggest that m A is generally not reversible, although m A may be susceptible to demethylation in pathophysiological states such as cancer.

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Rethinking m⁶A Readers, Writers, and Erasers

Cited by 857 publications

References 99 publications

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

Viral and cellular N6-methyladenosine and N6,2′-O-dimethyladenosine epitranscriptomes in the KSHV life cycle

FTO, m⁶A_m, and the hypothesis of reversible epitranscriptomic mRNA modifications

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Rethinking m6A Readers, Writers, and Erasers

Cited by 857 publications

References 99 publications

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K‐Akt signaling in gastric cancer

Viral and cellular N6-methyladenosine and N6,2′-O-dimethyladenosine epitranscriptomes in the KSHV life cycle

FTO, m6Am, and the hypothesis of reversible epitranscriptomic mRNA modifications

Contact Info

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Rethinking m⁶A Readers, Writers, and Erasers

FTO, m⁶A_m, and the hypothesis of reversible epitranscriptomic mRNA modifications