Mettl3-mediated mRNA m6A methylation promotes dendritic cell activation
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ABSTRACT:
PROVIDER: PRJNA423184 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5721550.fastq.gz | Fastqsanger.gz | |||
| SRR5721551.fastq.gz | Fastqsanger.gz | |||
| SRR5721553_1.fastq.gz | Fastqsanger.gz | |||
| SRR5721553_2.fastq.gz | Fastqsanger.gz | |||
| SRR5721554_1.fastq.gz | Fastqsanger.gz |
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Project description:Esophageal cancer is a lethal malignancy with high mortality rate, while the molecular mechanisms underlying esophageal cancer pathogenesis are stillis poorly understood. Here we found that the N6-methyladenosine (m6A) methyltransferase METTL3 is significantly up-regulated in esophageal squamous cell carcinoma (ESCC) and associated with poor patient prognosis. Depletion of METTL3 results in decreased ESCC growth and progression in vitro and in vivo. We further established ESCC initiation and progression models using Mettl3 conditional knockout mouse and revealed that Mettl3 mediated m6A modification is essential for promotes ESCC initiation and progression in vivo. Moreover, using METTL3 overexpression ESCC cell model and Mettl3 conditional knockin mouse model, we demonstrated the critical function of Mettl3 in promoting in vivo ESCC tumorigenesis in vitro and in vivo. Mechanistically, Mettl3 catalyzed m6A modification promotes NOTCH1 expression and the activation of Notch signaling pathway. Forced activation of Notch signaling pathway successfully rescues the growth, migration and invasion capacities of METTL3 depleted ESCC cells. Our data uncovered important mechanistical insights underlying ESCC tumorigenesis and provided molecular basis for the development of novel strategies for ESCC diagnosis and treatment.
2021-09-15 | GSE179267 | GEO
Project description:we find METTL3 associates with polyribosomes and promotes translation. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to the 3' untranslated region (UTR) of a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. m6A seq in A549 and H1299 cells, RNA seq in METTL3 knockdown cells
2016-07-03 | E-GEOD-76367 | biostudies-arrayexpress
Project description:XIST is a long non-coding RNA (lncRNA) that mediates transcriptional silencing of X chromosome genes. Here we show that XIST is highly methylated with at least 78 N6-methyladenosine (m6A) residues, a reversible base modification whose function in lncRNAs is unknown. We show that m6A formation in XIST, as well as cellular mRNAs, is mediated by RBM15 and its paralog RBM15B, which bind the m6A-methylation complex and recruit it to specific sites in RNA. This results in methylation of adenosines in adjacent m6A consensus motifs. Furthermore, knockdown of RBM15 and RBM15B, or knockdown of the m6A methyltransferase METTL3 impairs XIST-mediated gene silencing. A systematic comparison of m6A-binding proteins shows that YTHDC1 preferentially recognizes m6A in XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m6A. These data reveal a pathway of m6A formation and recognition required for XIST-mediated transcriptional repression. Three to four biological HEK293T replicates were used to perform iCLIP of endogenous YTH proteins, RBM15, and RBM15B. Crosslinking induced truncations were identified using CIMS-CITS pipeline.
2016-09-07 | E-GEOD-78030 | biostudies-arrayexpress
Project description:Background: N6-methyladenosine (m6A) RNA modification plays a crucial role in various biological events and is implicated in various metabolic-related diseases. However, its role in MASLD remains unclear. This study aims to investigate the impact of Mettl3 on MASLD through multi-omics analysis, with a focus on exploring its potential mechanisms of action. Methods: MASLD mouse models were established by feeding a high-fat diet for 12 weeks, and Mettl3 stable overexpression AML12 cell models were constructed via lentiviral transfection. Subsequent transcriptomic and proteomic analyses, as well as integrated analysis between different omics datasets, were conducted. Results: Mettl3 expression significantly increased in MASLD mouse models. In the transcriptomic and proteomic analyses, we identified 848 genes with significant inconsistencies between transcriptomic and proteomic datasets. GO/KEGG enrichment terms may involve post-transcriptional modifications, particularly Mettl3-mediated m6A modification. Subsequently, through integrated proteomic analysis of Mettl3-overexpressed AML12 cell models and MASLD mouse models, we selected the top 20 co-upregulated and co-downregulated GO/KEGG terms as the main biological processes influenced by Mettl3 in MASLD. By intersecting with pathways obtained from previous integrated analyses, we identified GO/KEGG terms affected by Mettl3-induced m6A modification. Protein-protein interaction analysis of proteins involved in these pathways highlighted GAPDH, ENO1, and TPI1 as three key hub genes. Conclusion: In MASLD, Mettl3 regulates the glycolytic pathway through m6A modification, influencing the occurrence and development of the disease via the key hub genes GAPDH, ENO1, and TPI1. These findings expand our understanding of MASLD and provide strong evidence for potential therapeutic targets and drug development.
2024-09-20 | PXD050565 | Pride
Project description:The N6-methyladenosine (m6A) mRNA modification and the mitochondrial respiratory chain (MRC) hold paramount importance in the advancement of MASLD. This study thoroughly investigates the relationship and impact of m6A mRNA modification and mitochondrial function in the progression of MASLD. Here we report that the mRNA and protein levels of mitochondrial respiratory chain (MRC) subunits showed inconsistent trends in vivo experiments. Abnormal m6A modification and mitochondrial dysfunction in MASLD were attributed to the upregulation of methyltransferase like 3 (Mettl3) and the downregulation of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) induced by high-fat foods. Mettl3 promoted the MRC's function. However, knockout of the reader protein YTHDF1, which plays a crucial role in the m6A modification process, counteracted the effect of Mettl3 and suppressed MRC. In MASLD, damage to the MRC may be regulated by the Mettl3-m6A-YTHDF1 complex axis, especially by the role of YTHDF1. Our research has offered a novel perspective on the involvement of m6A mRNA methylation in the pathogenesis of MASLD.
2024-09-20 | PXD047819 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-04-02 | GSE108333 | GEO
Project description:To study the effect of m6A modifications on subcellular mRNA localization we depleted m6A writer Mettl3 with shRNA and small molecule from mouse primary cortical neurons (mPCN) and sequenced neuritic and somatic compartments in parallel with scrambled shRNA control.
2023-07-12 | E-MTAB-11570 | biostudies-arrayexpress
Project description:N6-methyladenosine (m6A) RNA methylation is the most abundant modification on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex including methyltransferase like 3 (METTL3) as a key factor. However, the in vivo functions of METTL3 and m6A modification in mammalian development remain unclear. Here we show that specific inactivation of Mettl3 in mouse nervous system causes severe developmental defects in the brain. Mettl3 conditional knockout mice manifest cerebellar hypoplasia caused by drastically enhanced apoptosis of new born cerebellar granule cells (CGCs) in the external granular layer (EGL). METTL3 depletion induced loss of m6A modification causes extended RNA half-lives and aberrant splicing events, consequently leading to dysregulation of transcriptome-wide gene expression and premature CGC death. Our findings reveal a critical role of METTL3-mediated m6A in regulating the development of mammalian cerebellum.
2018-07-15 | GSE100528 | GEO
Project description:Genomic and transcriptomic alterations are insufficient to explain the variance in protein expression seen in cancer. Recent evidence has highlighted the role of N6-methyladenosine (m6A) in the regulation of mRNA expression, stability and translation, supporting a potential role for post-transcriptional regulation mediated by m6A in cancer. Here we explore prostate cancer as an exemplar cancer and generate the first prostate m6A maps, and further examined how low levels of N6-adenosine-methyltransferase (METTL3) associates with advanced prostate cancer and results in altered expression at the level of transcription, translation, and protein. In particular extracellular matrix proteins have a high number of m6A sites and show significant changes in expression with METTL3 knock-down. We also discovered the upregulation of a hepatocyte nuclear factor-driven gene signature that is associated with therapy resistance in prostate cancer. Significantly, METTL3 knock-down rendered the cells resistant to androgen receptor antagonists, implicating changes in m6A as a mechanism for therapy resistance in metastatic prostate cancer.
2021-06-07 | PXD022348 | Pride
Project description:Methyltransferase-like 3 (METTL3) is the predominant catalytic enzyme which forms a stable complex with METTL14 and WTAP to promote m6A methylation in the nucleus. Recently, accumulating evidence has shown that METTL3 can express in the cytoplasm but the function of cytoplasmic METTL3 is not fully understood. Here, we demonstrated that METTL3 inhibition significantly delayed tumorigenesis in gastric cancer both in and ex vivo. Surprisingly, our data revealed that METTL3 could not only facilitate cancer progression via mRNA m6A modification, but also bind to numerous non-m6A-modified mRNAs, suggesting an unexpected role of METTL3 that was independent of m6A modification. Mechanistically, cytoplasm-anchored METTL3 interacted with poly(A) binding protein cytoplasmic 1 (PABPC1) to stabilize its association with cap-binding complex eIF4F, which preferentially promoted the translation of epigenetic factors without m6A modification. Clinical investigation using both xenograft models and patient samples showed that cytoplasmic distributed METTL3 was highly correlated with gastric cancer progression, and this finding could be expanded in prostate cancer patients. We therefore propose that cytoplasmic METTL3 enhances the translation of both m6A and non-m6A-modified epigenetic mRNAs thus serves as an oncogenic driver in cancer progression, and METTL3 subcellular distribution can assist diagnose and predict prognosis for cancer patients.
2022-05-16 | GSE191170 | GEO