Post-transcriptional gene regulation by mRNA modifications

Zhao, Boxuan Simen; Roundtree, Ian A.; He, Chuan

doi:10.1038/nrm.2016.132

Cited by 1,755 publications

(1,854 citation statements)

References 181 publications

(216 reference statements)

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“…Although its existence was first reported 40 years ago 2, the biological function and significance of m6A modification have only recently entered the research spotlight. The abundance of m6A has been shown to be approximately 0.1–0.4% of the total adenosine residues in cellular mRNA, and the average content of m6A has been estimated to be three to five residues per mammalian mRNA 10. 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.…”

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

164

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

164

148

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“…Regulatory RNA modifications include A‐to‐I editing, pseudouridylation, methylation, and nicotinamide‐adenine dinucleotide (NAD + ) capping, which can regulate many cellular processes by influencing RNA metabolism (Jiao et al., 2017; Nishikura, 2016; Walters et al., 2016; Wang et al., 2014; Zhao, Roundtree & He, 2017). For example, A‐to‐I editing within a coding region of mRNA may lead to abnormal protein expressions that are not encoded in the genome, and editing within intronic regions could create new splice sites resulting in the inclusion of an undesired sequence in the mature mRNA (Nishikura, 2016).…”

Section: Introductionmentioning

confidence: 99%

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

et al. 2018

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SummaryGene expression is dynamically regulated in a variety of mammalian physiologies. During mammalian aging, there are changes that occur in protein expression that are highly controlled by the regulatory steps in transcription, post‐transcription, and post‐translation. Although there are global profiles of human transcripts during the aging processes available, the mechanism(s) by which transcripts are differentially expressed between young and old cohorts remains unclear. Here, we report on N6‐methyladenosine (m6A) RNA modification profiles of human peripheral blood mononuclear cells (PBMCs) from young and old cohorts. An m6A RNA profile identified a decrease in overall RNA methylation during the aging process as well as the predominant modification on proteincoding mRNAs. The m6A‐modified transcripts tend to be more highly expressed than nonmodified ones. Among the many methylated mRNAs, those of DROSHA and AGO2 were heavily methylated in young PBMCs which coincided with a decreased steady‐state level of AGO2 mRNA in the old PBMC cohort. Similarly, downregulation of AGO2 in proliferating human diploid fibroblasts (HDFs) also correlated with a decrease in AGO2 mRNA modifications and steady‐state levels. In addition, the overexpression of RNA methyltransferases stabilized AGO2 mRNA but not DROSHA and DICER1 mRNA in HDFs. Moreover, the abundance of miRNAs also changed in the young and old PBMCs which are possibly due to a correlation with AGO2 expression as observed in AGO2‐depleted HDFs. Taken together, we uncovered the role of mRNA methylation on the abundance of AGO2 mRNA resulting in the repression of miRNA expression during the process of human aging.

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“…In the past few years, He's group has discovered evidence 14 suggesting that RNA modifications provide a way to regulate transcripts involved in broad cellular roles, such as switching on cell-differentiation programs. Researchers need better technologies to explore these links; and, in October 2016, the US National Institutes of Health awarded He and Pan a 5-year, US$10.6-million grant to establish a centre to develop methods for identifying and mapping RNA modifications.…”

Section: Enhancing the Toolboxmentioning

confidence: 99%

The RNA code comes into focus

Rae¹

2017

Nature

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As researchers open up to the reality of RNA modification, an expanded epitranscriptomics toolbox takes shape. THE RNA CODE COMES INTO FOCUSBY K E L LY R A E C H I I n 2004, oncologist Gideon Rechavi at Tel Aviv University in Israel and his colleagues compared all the human genomic DNA sequences then available with their corresponding messenger RNAs -the molecules that carry the information needed to make a protein from a gene. They were looking for signs that one of the nucleotide building blocks in the RNA sequence, called adenosine (A), had changed to another building block called inosine (I). This ' A-to-I editing' can alter a protein's coding sequence, and, in humans, is crucial for keeping the innate immune response in check. "It sounds simple, but in real life it was really complicated," Rechavi recalls. "Several groups had tried it before and failed" because sequencing mistakes and single-nucleotide mutations had made the data noisy. But using a new bioinformatics approach, his team uncovered thousands of sites in the transcriptome -the complete set of mRNAs found in an organism or cell population -and later studies upped the number into the millions 1 . Inosine is something of a special case: researchers can readily detect this chink in the armour by comparing DNA and RNA sequences. But at least one-quarter of our mRNAs harbour chemical tags -decorations to the A, C, G and U nucleotides -that are invisible to today's sequencing technologies. (Similar chemical tags, called epigenetic markers, are also found on DNA.) Researchers aren't sure what these chemical changes in RNA do, but they're trying to find out.A wave of studies over the past five yearsmany of which focus on a specific RNA mark called N 6 -methyladenosine (m 6 A) -have mapped these alterations across transcriptomes and demonstrated their importance to health and disease. But the problem is vast: these marks coat not only mRNA but other RNA transcripts as well, and they cut across TECHNOLOGY FEATURE © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Post-transcriptional gene regulation by mRNA modifications

Cited by 1,755 publications

References 181 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

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

The RNA code comes into focus

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