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MRNA circularization by METTL3-eIF3h enhances translation

ABSTRACT: N6-methyladenosine (m6A) modification of mRNA catalyzed by METTL3 is enriched at a subset of stop codons. METTL3 can promote translation but the mechanism and widespread relevance remain unknown. Here we show that METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon supporting a mRNA looping mechanism for ribosome recycling and translational control. Electron microscopy revealed the topology of individual polyribosomes with single METTL3 foci found in close proximity to 5’ cap-binding proteins. We identify a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). METTL3 promotes translation of a large subset of oncogenic mRNAs, including BRD4 that are also m6A-modified in human primary lung tumors. The METTL3-eIF3h interaction is required for enhanced translation, formation of densely packed polyribosomes, and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. These findings uncover a mRNA looping mechanism of translation control and identify METTL3-eIF3h as a potential cancer therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117299 | GEO | 2018/09/21

REPOSITORIES: GEO

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METTL3 promotes translation in human cancer cells

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

METTL3 promotes translation in human cancer cells

2016-01-01 | GSE76367 | GEO

mRNA circularization by METTL3-eIF3h enhances translation

Project description:mRNA circularization by METTL3-eIF3h enhances translation

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METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumorigenesis (meRIP, RIP and polysome-seq)

Project description:Methyltransferase-like 3 (METTL3) is the best known m6A methyltransferase of the N6-adenosine-methyltransferase complex that functions in the reversible epi-transcriptome modulation of m6A modification. Besides acting as a m6A methyltransferase, METTL3 also regulates mRNA translation as well as other biological processes either through m6A “reader”-mediated downstream effect or directly binding to m6A sites, but the underlying mechanism and biological significance of these cytoplasmic events remain undefined. Here, we demonstrated that METTL3 inhibition significantly delayed gastric tumorigenesis in patient-derived xenograft model. Intriguingly, global METTL3-binding profiling revealed METTL3 occupied numerous oncogenic mRNAs without m6A signals, indicating a novel mechanism independent of m6A machinery. Furthermore, METTL3 was observed to translocate from nucleus to cytoplasm during gastric carcinogenesis, and its cytoplasm-to-nucleus ratio was correlated with cancer progression. In addition, the nuclear retention of METTL3 nearly abolished its tumor-promoting activity. Mechanistically, METTL3 interacted with PABPC1 to promote RNA looping, thus facilitating the translation of multiple oncogenic mRNAs. Taken together, our findings indicate an unexpected role of METTL3 as an important translational regulator independent of either m6A-“writer” or -“reader” activities and suggest METTL3 as a therapeutic target in gastric cancer.

2022-05-16 | GSE163310 | GEO

m6A RNA Methylation is Critical for Adequate Exit from Naïve Pluripotency and Execution of Mammalian Development (Ribo-seq)

Project description:In this study we identify Mettl3, an m6A RNA modification writer, as a critical regulator for terminating naïve pluripotency and a positive maintainer of primed pluripotency in vitro and in vivo. Remarkably, Mettl3 knockout pre-implantation epiblasts and naïve ES cells, entirely lack m6A on coding mRNAs and are viable. Yet, they fail to adequately terminate the naïve pluripotent state, and subsequently undergo aberrant priming and early lineage commitment at the post-implantation stage. A comprehensive functional and genomic analysis involving profiling of m6A, RNA transcription and translation in Mettl3 wild-type and knockout pluripotent and differentiated cells, identified m6A as a critical determinant that destabilizes secondary naïve specific pluripotency genes Esrrb, Klf4 and Nanog, and restrains their transcript stability and translation efficiency. In summary, our findings provide for the first time evidence for a critical role for an mRNA epigenetic modification in early mammalian development in vivo, and identify a mechanism that functionally regulates mouse naïve and primed pluripotency in an opposing manner. Ribosome footprint (Ribo-Seq) was measured from mouse embryonic stem cells and mouse embriod bodies, in WT and Mettl3-KO cell lines.

2014-11-02 | E-GEOD-61996 | biostudies-arrayexpress

Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-low Induction of Therapy Resistance

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

m6A RNA Methylation is Critical for Adequate Exit from NaM-CM-/ve Pluripotency and Execution of Mammalian Development (3p-Seq)

Project description:In this study we identify Mettl3, an m6A RNA modification writer, as a critical regulator for terminating naM-CM-/ve pluripotency and a positive maintainer of primed pluripotency in vitro and in vivo. Remarkably, Mettl3 knockout pre-implantation epiblasts and naM-CM-/ve ES cells, entirely lack m6A on coding mRNAs and are viable. Yet, they fail to adequately terminate the naM-CM-/ve pluripotent state, and subsequently undergo aberrant priming and early lineage commitment at the post-implantation stage. A comprehensive functional and genomic analysis involving profiling of m6A, RNA transcription and translation in Mettl3 wild-type and knockout pluripotent and differentiated cells, identified m6A as a critical determinant that destabilizes secondary naM-CM-/ve specific pluripotency genes Esrrb, Klf4 and Nanog, and restrains their transcript stability and translation efficiency. In summary, our findings provide for the first time evidence for a critical role for an mRNA epigenetic modification in early mammalian development in vivo, and identify a mechanism that functionally regulates mouse naM-CM-/ve and primed pluripotency in an opposing manner. 3' polyA RNA-sequencing (equivalent to Digital Gene Expression) measured in mouse Embryonic Stem Cells (ESCs) and mouse Embriod bodies (EBs) 0,4 & 8 hours after treatment with Actinomycin which halts transcription. Measured in both WT and Mettl3-KO cells.

2014-11-02 | E-GEOD-61994 | biostudies-arrayexpress

m6A RNA Methylation is Critical for Adequate Exit from NaM-CM-/ve Pluripotency and Execution of Mammalian Development (m6a-seq)

Project description:In this study we identify Mettl3, an m6A RNA modification writer, as a critical regulator for terminating naM-CM-/ve pluripotency and a positive maintainer of primed pluripotency in vitro and in vivo. Remarkably, Mettl3 knockout pre-implantation epiblasts and naM-CM-/ve ES cells, entirely lack m6A on coding mRNAs and are viable. Yet, they fail to adequately terminate the naM-CM-/ve pluripotent state, and subsequently undergo aberrant priming and early lineage commitment at the post-implantation stage. A comprehensive functional and genomic analysis involving profiling of m6A, RNA transcription and translation in Mettl3 wild-type and knockout pluripotent and differentiated cells, identified m6A as a critical determinant that destabilizes secondary naM-CM-/ve specific pluripotency genes Esrrb, Klf4 and Nanog, and restrains their transcript stability and translation efficiency. In summary, our findings provide for the first time evidence for a critical role for an mRNA epigenetic modification in early mammalian development in vivo, and identify a mechanism that functionally regulates mouse naM-CM-/ve and primed pluripotency in an opposing manner. m6A-seq was measured from total RNA in mouse embryonic stem cells (ESCs), embroid bodies (EBs) and embronic fibroblasts (MEF). 3 biological replicates are available from BVSC ESC line and EBs, and two biological replicates are available for MEFs. Each sample consist of IP to m6A and control input

2014-11-02 | E-GEOD-61995 | biostudies-arrayexpress

m6A RNA Methylation is Critical for Adequate Exit from Naïve Pluripotency and Execution of Mammalian Development (RNA-Seq)

Project description:In this study we identify Mettl3, an m6A RNA modification writer, as a critical regulator for terminating naïve pluripotency and a positive maintainer of primed pluripotency in vitro and in vivo. Remarkably, Mettl3 knockout pre-implantation epiblasts and naïve ES cells, entirely lack m6A on coding mRNAs and are viable. Yet, they fail to adequately terminate the naïve pluripotent state, and subsequently undergo aberrant priming and early lineage commitment at the post-implantation stage. A comprehensive functional and genomic analysis involving profiling of m6A, RNA transcription and translation in Mettl3 wild-type and knockout pluripotent and differentiated cells, identified m6A as a critical determinant that destabilizes secondary naïve specific pluripotency genes Esrrb, Klf4 and Nanog, and restrains their transcript stability and translation efficiency. In summary, our findings provide for the first time evidence for a critical role for an mRNA epigenetic modification in early mammalian development in vivo, and identify a mechanism that functionally regulates mouse naïve and primed pluripotency in an opposing manner. polyA RNA-seq was measured in mouse embryonic stem cells (ESCs) and embroid bodies (EBs), each in WT and in Mettl3-KO cell lines. RNA-seq was measured also from WT mouse embronic fibroblasts (MEF). 3 biological replicates are available from ESCs and 2 from EBs. Replicate C in ESCs was measured alongside protein levels (SILAC) and was used for the analysis of that assay.

2014-11-02 | E-GEOD-61997 | biostudies-arrayexpress

BET inhibition abrogates global transcription via repressing m6A writer complex

Project description:To characterize the role of m6A modification in mediating BRD4-dependent biological functions, we established METTL3 reconstituting cells and treated with JQ1 BRD4 directs gene transcription through diverse mechanisms. Here, we specifically focused on BETi-dependent transcriptome or chestrated by m6A-mediated regulation. To this end, we first need to identify bona fide m6A-dependent transcripts via rescue experiments in METTL3-knockdown cells by adding back wild-type METTL3 or METTL3-CD mutant (a catalytically inactive form of METTL3)

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