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N6-Adenosine methylation regulates the translation of insulin mRNA

ABSTRACT: Relatively little is known about the first step of insulin synthesis: the translation of the mRNA. Here we show that the translation of D. melanogaster insulin 2 mRNA (dilp2) is controlled by methylation of N6-adenosine (m6A) in the 3’ UTR. Mutations in the m6A writer Mettl3 and methylated residues in the dilp2 3’UTR decreased the levels of dilp2 mRNA associated with the polysomes and the total amount of dilp2 protein produced. This resulted in aberrant energy homeostasis and diabetic-like phenotypes consistent with the specific function of dilp2 in adult metabolism. Conserved m6A signatures were also identified in the 3’ UTRs of vertebrate insulin mRNAs. These data identify m6A as a key regulator of insulin protein synthesis and energy homeostasis in metazoans with important implications for diabetes and metabolic disease.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE207547 | GEO | 2023/04/25

REPOSITORIES: GEO

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N6-methyl adenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis

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2017-08-22 | PXD006498 | Pride

m6A in 5â untranslated regions promotes cap-independent translation of mRNA

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mRNA-seq of neuronal compartments in shRNA-mediated + small-molecule knockdown of Mettl3 in mouse primary cortical neurons (mPCN)

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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

Light-induced LLPS of the CRY2/SPA1/FIO1 complex regulating mRNA methylation and chlorophyll homeostasis in Arabidopsis

Project description:Light regulates chlorophyll homeostasis and photosynthesis via various molecular mechanisms in plants. The light regulation of transcription and protein stability of nuclear-encoded chloroplast proteins have been extensively studied, but how light regulation of mRNA metabolism affects abundance of nuclear-encoded chloroplast proteins and chlorophyll homeostasis remains poorly understood. Here we show that the blue light receptor cryptochrome 2 (CRY2) and the METTL16-type m6A writer FIONA1 (FIO1) regulate chlorophyll homeostasis in response to blue light. In contrast to the CRY2-mediated photo-condensation of the mRNA adenosine methylase (MTA), photoexcited CRY2 co-condenses FIO1 only in the presence of the CRY2-signalling protein SUPPRESSOR of PHYTOCHROME A (SPA1). CRY2 and SPA1 synergistically or additively activate the RNA methyltransferase activity of FIO1 in vitro, whereas CRY2 and FIO1, but not MTA, are required for the light-induced methylation and translation of the mRNAs encoding multiple chlorophyll homeostasis regulators in vivo. Our study demonstrates that the light-induced liquid-liquid phase separation of the photoreceptor/writer complexes is commonly involved in the regulation of photoresponsive changes of mRNA methylation, whereas the different photo-condensation mechanisms of the CRY/FIO1 and CRY/MTA complexes explain, at least partially, the writer-specific functions in plant photomorphogenesis.

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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

Targeted Quantitative Profiling of Epitranscriptomic Reader, Writer and Eraser Proteins Revealed Potential Crosstalk between N6-Methyladenosine and Other RNA Modifications

Project description:N⁶-methyladenosine (m6A) and its reader, writer, and eraser (RWE) proteins assume crucial roles in regulating the splicing, stability, and translation of mRNA. To our knowledge, no systematic investigations have been conducted about the crosstalk between m6A and other modified nucleosides in RNA. Herein, we modified our recently established liquid chromatography-parallel-reaction monitoring (LC-PRM) method by incorporating stable isotope-labeled (SIL) peptides as internal or surrogate standards for profiling epitranscriptomic RWE proteins. We were able to detect reproducibly a total of 114 RWE proteins in HEK293T cells with the genes encoding m6A eraser proteins (i.e., ALKBH5, FTO) and the catalytic subunit of the major m6A writer complex (i.e., METTL3) being individually ablated. Notably, eight proteins were altered by more than 1.5-fold in the opposite directions in HEK293T cells depleted of METTL3 and ALKBH5. Analysis of published m6A mapping results revealed the presence of m6A in the corresponding mRNAs of four of these proteins. Together, we integrated SIL peptides into our LC-PRM method for quantifying epitranscriptomic RWE proteins, and our work revealed potential crosstalks between m6A and other epitranscriptomic modifications. Our modified LC-PRM method with the use of SIL peptides should be applicable for high-throughput profiling of epitranscriptomic RWE proteins in other cell types and in tissues.

2022-09-24 | PXD036032 | Pride

Scope and mechanism of eIF4F-independent mRNA translation

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