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Combined analysis of ribo-seq and rna-seq reveals that Mettl3 regulates embryonic cerebral cortex development in mice by controlling the proliferation and differentiation of neural progenitor cells

ABSTRACT: N6-methyladenosine (m6A) is the most important internal messenger RNA (mRNA) modification in mammals. The role of Mettl3, the core component of methyltransferase, and Fto, the demethylase, has not been revealed in the embryonic development of the cerebral cortex in mice. We constructed the conditional knockout of Mettl3 and Fto in the cerebral cortex of mice. We found that Mettl3 deletion causes cell cycle extension of progenitors and massive proliferation of intermediate progenitors at E15.5, which lead to a fold structure of cortex, while Fto deletion hardly altered cell numbers or morphology. Meanwhile, both transcriptome sequence (RNA-Seq) and ribosome profiling (Ribo-Seq) of Mettl3-deleted cortex mRNAs in E15.5 revealed that the differential genes were enriched in cell differentiation, neurogenesis, neuron differentiation, cell proliferation, and cell cycle. Moreover, deleted Mettl3 but not Fto significantly upregulated Ythdf1 and Ythdf2, which caused a substantial change in gene translation efficiency. Our findings indicate cortex m6A represents a novel layer of complexity in gene expression regulation and provide a new mechanism of precisely programmed RNA maturation.

ORGANISM(S): Mus musculus

PROVIDER: GSE154992 | GEO | 2021/01/04

REPOSITORIES: GEO

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Mettl3-m6A-YTHDF1 axis promotion of mitochondrial dysfunction in metabolic dysfunction–associated steatotic liver disease (MASLD)

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TBK1-METTL3 axis facilitates antiviral immunity [RNA-seq: Mock or VSV treated WT and Ythdf1-KO BMDM]

Project description:mRNA m6A modification is involved in regulation of immune system. However, its function in antiviral immunity is controversial, and how immune responses regulate m6A modification is unknown. We here found TBK1, a key kinase of antiviral pathways, phosphorylated the core m6A methyltransferase METTL3 at Serine 67. The phosphorylated METTL3 interacted with translational complex and enhanced proteins translation, including IRF3, and facilitated antiviral responses. TBK1 also promoted METTL3 activation and m6A modification, which is required for stabilizing IRF3 mRNA. Type I IFN induction was severely impaired in METTL3 deficient cells. Mettl3flfl-lyz2-Cre mice were significantly more susceptible to IAV-induced lethality than control mice. Consistently, Ythdf1—/— mice cannot control viral infection and showed higher mortality than control mice due to decreased IRF3 expression. Together, we demonstrated that innate signals activated METTL3 via TBK1, and METTL3 and m6A modification secured antiviral immunity by promoting mRNA stability and protein translation.

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TBK1-METTL3 axis facilitates antiviral immunity [RNA-seq: Brain from WT and Mettl3 heterozygous kd]

Project description:mRNA m6A modification is involved in regulation of immune system. However, its function in antiviral immunity is controversial, and how immune responses regulate m6A modification is unknown. We here found TBK1, a key kinase of antiviral pathways, phosphorylated the core m6A methyltransferase METTL3 at Serine 67. The phosphorylated METTL3 interacted with translational complex and enhanced proteins translation, including IRF3, and facilitated antiviral responses. TBK1 also promoted METTL3 activation and m6A modification, which is required for stabilizing IRF3 mRNA. Type I IFN induction was severely impaired in METTL3 deficient cells. Mettl3flfl-lyz2-Cre mice were significantly more susceptible to IAV-induced lethality than control mice. Consistently, Ythdf1-/- mice cannot control viral infection and showed higher mortality than control mice due to decreased IRF3 expression. Together, we demonstrated that innate signals activated METTL3 via TBK1, and METTL3 and m6A modification secured antiviral immunity by promoting mRNA stability and protein translation.

2020-10-14 | GSE159421 | GEO

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