m6A modification controls the innate immune response to infection by targeting type I interferons

Winkler, Roni; Gillis, Ella; Lasman, Lior; Safra, Modi; Geula, Shay; Soyris, Clara; Nachshon, Aharon; Tai-Schmiedel, Julie; Friedman, Nehemya; Le‐Trilling, Vu Thuy Khanh; Trilling, Mirko; Mandelboim, Michal; Hanna, Jacob; Schwartz, Schraga

doi:10.1038/s41590-018-0275-z

Cited by 372 publications

(411 citation statements)

References 57 publications

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“…Transcript levels of IFNA/IFNB/IFNG/ISG15 were upregulated by METTL14/YTHDF1 knockdown in both AGS and HGC27 cells ( Figure S4D). While according to ELISA assay, the levels of secreted interferon α/β/γ proteins in HGC27 were slightly upregulated by METTL14/YTHDF1 knockdown, or downregulated by FTO knockdown (Figure S4E), which was in accordance with the findings of Winkler et al 29 Since interferons exerted dual functions in mediating cancer immunity, m6A may modulate immune responses of GC through repressing interferon production ( Figure 5C). However, due to the illegibility of current data, whether RNA m6A modification regulates interferon/immune response of GC remains to be validated, and m6A's linkage with immunotherapy deserved further investigation.…”

Section: M6a Modification Was Potentially Correlated With Immunothesupporting

confidence: 88%

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: M6a Modification Was Potentially Correlated With Immunothesupporting

confidence: 88%

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

et al. 2019

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“…There are many techniques used to determine a single RNA modification in a cell type and biology of choice. Site-specific Cleavage and Radioactive-labeling followed by ligation-assisted extraction and TLC (SCARLET) Technology give scientists the ability to probe for N6-methyladenosine RNA (m6A) modification status at single nucleotide resolution in mRNA and long noncoding RNA [266]. The significance of RNA modifications to the control of the immune response is beginning to be appreciated.…”

Section: Rna Modifications Of Lncrnasmentioning

confidence: 99%

The how and why of lncRNA function: An innate immune perspective

Robinson

Covarrubias

2020

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

237

192

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“…The functional abrogation of METTL3 or METTL14 leads to the overproduction of IFN‐β and IFN‐stimulated genes (ISGs) in response to double‐stranded DNA (dsDNA) exposure, and better control of human cytomegalovirus infection, while the knockdown of the m 6 A demethylase ALKBH5 has the opposite effect. Mechanistically, Roni and colleagues reported that m 6 A deposition mediates the destabilisation of IFNB mRNA by YTHDF2 . In contrast, Rubio and colleagues described a reduction of IFN‐β production upon YTHDF1 or YTHDF2 knockdown .…”

Section: Inflammation‐related Mrnas Are Regulated By a Set Of Rna Binmentioning

confidence: 99%

“…Recently, several groups have demonstrated that m 6 A deposition regulates the production of IFN-b. 54,55 The functional abrogation of METTL3 or METTL14 leads to the overproduction of IFN-b and IFN-stimulated genes (ISGs) in response to doublestranded DNA (dsDNA) exposure, and better control of human cytomegalovirus infection, while the knockdown of the m 6 A demethylase ALKBH5 has the opposite effect. Mechanistically, Roni and colleagues reported that m 6 A deposition mediates the destabilisation of IFNB mRNA by YTHDF2.…”

Section: Rna Modifications Deposited By Rbpsmentioning

confidence: 99%

Post‐transcriptional control of immune responses and its potential application

Yoshinaga

Takeuchi

2019

Clin & Trans Imm

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Inflammation is the host response against stresses such as infection. Although the inflammation process is required for the elimination of pathogens, uncontrolled inflammation leads to tissue destruction and inflammatory diseases. To avoid this, the inflammatory response is tightly controlled by multiple layers of regulation. Post‐transcriptional control of inflammatory mRNAs is increasingly understood to perform critical roles in this process. This is mediated primarily by a set of RNA binding proteins (RBPs) including tristetraprolin, Roquin and Regnase‐1, and RNA methylases. These key regulators coordinate the inflammatory response by modulating mRNA pools in both immune and local nonimmune cells. In this review, we provide an overview of the post‐transcriptional coordination of immune responses in various tissues and discuss how RBP‐mediated regulation of inflammation may be harnessed as a potential class of treatments for inflammatory diseases.

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m6A modification controls the innate immune response to infection by targeting type I interferons

Cited by 372 publications

References 57 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

The how and why of lncRNA function: An innate immune perspective

Post‐transcriptional control of immune responses and its potential application

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