Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism

Yang, Ying; Hsu, Phillip J.; Chen, Yu‐Sheng; Yang, Yun‐Gui

doi:10.1038/s41422-018-0040-8

Cited by 1,133 publications

(1,473 citation statements)

References 147 publications

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“…N6‐adenosine methylation (m6A) of RNA transcripts is the most prevalent modification found in many classes of RNA . Similar to epigenetic changes in DNA and histone modifications, m6A in RNA is dynamic and reversible . In all classes of RNA, m6A mainly occurs within a highly‐conserved consensus motif identified as RRACH (R=G or A, H=A, C or U).…”

Section: Introductionmentioning

confidence: 99%

Changes in m6A RNA methylation contribute to heart failure progression by modulating translation

Berulava

Buchholz

Vakhtang

et al. 2019

European J of Heart Fail

230

235

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Aims Deregulation of epigenetic processes and aberrant gene expression are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA methylation in heart failure development. Methods and results We analysed m6A RNA methylation via next‐generation sequencing. We found that approximately one quarter of the transcripts in the healthy mouse and human heart exhibit m6A RNA methylation. During progression to heart failure we observed that changes in m6A RNA methylation exceed changes in gene expression both in mouse and human. RNAs with altered m6A RNA methylation were mainly linked to metabolic and regulatory pathways, while changes in RNA expression level mainly represented changes in structural plasticity. Mechanistically, we could link m6A RNA methylation to altered RNA translation and protein production. Interestingly, differentially methylated but not differentially expressed RNAs showed differential polysomal occupancy, indicating transcription‐independent modulation of translation. Furthermore, mice with a cardiomyocyte restricted knockout of the RNA demethylase Fto exhibited an impaired cardiac function compared to control mice. Conclusions We could show that m6A landscape is altered in heart hypertrophy and heart failure. m6A RNA methylation changes lead to changes in protein abundance, unconnected to mRNA levels. This uncovers a new transcription‐independent mechanisms of translation regulation. Therefore, our data suggest that modulation of epitranscriptomic processes such as m6A methylation might be an interesting target for therapeutic interventions.

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Section: Introductionmentioning

confidence: 99%

Changes in m6A RNA methylation contribute to heart failure progression by modulating translation

Berulava

Buchholz

Vakhtang

et al. 2019

European J of Heart Fail

230

235

View full text Add to dashboard Cite

show abstract

“…N6‐methyladenosine (m6A) is the most abundant internal modification of mRNA and long noncoding RNA in most eukaryotes . N6‐methyladenosine plays an important role in regulating mRNA splicing, translation, and stability . It is methylated on the sixth position of N on adenosine, mainly in the CDS region and 3′ untranslated regions region of the mRNA, affecting mRNA stability, translation efficiency, variable splicing, and localization.…”

Section: Introductionmentioning

confidence: 99%

Identification of three m6A‐related mRNAs signature and risk score for the prognostication of hepatocellular carcinoma

et al. 2020

Cancer Medicine

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Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is extremely harmful to human health. In recent years, N6‐methyladenosine (m6A) RNA methylation in eukaryotic mRNA has been increasingly implicated in cancer pathogenesis and prognosis. In this study, we downloaded the expression profile and clinical information of 307 patients from The Cancer Genome Atlas database and 64 patients from the Gene Expression Omnibus (GEO) database, and univariate Cox analysis revealed that METTL14 was a prognostic m6A RNA methylation regulator. For further study on the related genes of METTL14, weighted gene co‐expression network analysis was used to find the relationship between METTL14 and gene expression, and univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) methods were used to identify hub genes that may be associated with HCC prognosis. The results indicated that cysteine sulfinic acid decarboxylase, glutamic‐oxaloacetic transaminase 2, and suppressor of cytokine signaling 2 were key genes affecting the prognosis of HCC patients, and m6A methylation of these mRNAs may be regulated by METTL14. Finally, a nomogram was constructed based on the hub gene expression levels, and its prediction accuracy and discriminative ability were measured by the C‐index and a calibration curve. In conclusion, METTL14, an m6A RNA methylation regulator, may participate in the malignant progression of HCC by adjusting the m6A of cysteine sulfinic acid decarboxylase, glutamic‐oxaloacetic transaminase 2, and suppressor of cytokine signaling 2, and these genes are useful for prognostic stratification and treatment strategy development.

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“…4,5 Methylated RNA immunoprecipitation followed by sequencing (MeRIP-Seq) is an epitranscriptome-wide assay to determine the presence of m 6 A. 2 Furthermore, several m 6 A regulators have been reported, such as the methylating enzyme m 6 A writer protein (METTL3, METTL14, and WTAP), 8 the demethylating enzyme m 6 A eraser protein (FTO, ALKBH5), 9 and m 6 A reader proteins (YTH family), that recognize m 6 A. 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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Intracellular mRNA levels are not always proportional to their respective protein levels, especially in the placenta. This discrepancy may be attributed to various factors including post-transcriptional regulation, such as mRNA methylation (N6methyladenosine: m 6 A). Here, we conducted a comprehensive m 6 A analysis of human placental tissue from neonates with various birth weights to clarify the involvement of m 6 A in placental biology. The augmented m 6 A levels at the 5′-untranslated region (UTR) in mRNAs of small-for-date placenta samples were dominant compared to reduction of m 6 A levels, whereas a decrease in m 6 A in the vicinity of stop codons was common in heavy-for-date placenta samples. Notably, most of these genes showed similar expression levels between the different birth weight categories. In particular, preeclampsia placenta samples showed consistently upregulated SMPD1 protein levels and increased m 6 A at 5′-UTR but did not show increased mRNA levels. Mutagenesis of adenosines at 5′-UTR of SMPD1 mRNAs actually decreased protein levels in luciferase assay. Collectively, our findings suggest that m 6 A both at the 5′-UTR and in the vicinity of stop codon in placental mRNA may play important roles in fetal growth and disease.

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Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism

Cited by 1,133 publications

References 147 publications

Changes in m6A RNA methylation contribute to heart failure progression by modulating translation

Changes in m6A RNA methylation contribute to heart failure progression by modulating translation

Identification of three m6A‐related mRNAs signature and risk score for the prognostication of hepatocellular carcinoma

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

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