Dataset Information

METTL3-mediated m6A modification is required for cerebellar development.

ABSTRACT: 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 (cKO) mice manifest cerebellar hypoplasia caused by drastically enhanced apoptosis of newborn 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.

SUBMITTER: Wang CX

PROVIDER: S-EPMC6021109 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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METTL3-mediated m6A modification is required for cerebellar development.

Wang Chen-Xin CX Cui Guan-Shen GS Liu Xiuying X Xu Kai K Wang Meng M Zhang Xin-Xin XX Jiang Li-Yuan LY Li Ang A Yang Ying Y Lai Wei-Yi WY Sun Bao-Fa BF Jiang Gui-Bin GB Wang Hai-Lin HL Tong Wei-Min WM Li Wei W Wang Xiu-Jie XJ Yang Yun-Gui YG Zhou Qi Q

PLoS biology 20180607 6

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. Met ...[more]

PMID: 29879109

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Project description:BackgroundDCLRE1B is a 5'-to-3' exonuclease, which is involved in repairing ICL-related DNA damage. DCLRE1B has been reported to cause poor prognosis in a variety of cancers. Nonetheless, there is no research on DCLRE1B's biological role in pan-cancer datasets. Thus, ascertaining the processes via which DCLRE1B modulates tumorigenesis was the goal of the extensive bioinformatics investigation of pan-cancer datasets in the present research.MethodsIn our research, employing internet websites and databases including TIMER, GEPIA, TISIDB, Kaplan-Meier Plotter, SangerBox, cBioPortal, and LinkedOmics, DCLRE1B-related data in numerous tumors were extracted. To ascertain the association among DCLRE1B expression, prognosis, genetic changes, and tumor immunity, the pan-cancer datasets were examined. The DCLRE1B's biological roles in pancreatic cancer cells were ascertained by employing wound healing, in vitro CCK-8, and MeRIP-qPCR assays.ResultAccording to the pan-cancer analysis, in numerous solid tumors, DCLRE1B upregulation was observed. Expression of DCLRE1B was found to be substantially related to the cancer patients' prognoses. Similarly, expression of DCLRE1B exhibited substantial association with immune cells in several cancer types. DCLRE1B expression correlated with immune checkpoint (ICP) gene expression and impacted immunotherapy sensitivity. According to in vitro trials, DCLRE1B promoted PC cells' proliferation and migration capacities. Also, according to GSEA enrichment analysis, DCLRE1B might participate in the JAK-STAT signaling pathway, which was confirmed by western blotting. In addition, we also found that the downregulation of DCLRE1B may be regulated by METTL3-mediated m6A modification.ConclusionsIn human cancer, the overexpression of DCLRE1B was generally observed, which aided cancer onset and advancement via a variety of processes comprising control of the immune cells' tumor infiltration. According to this study's findings, in a few malignant tumors, DCLRE1B is a candidate immunotherapeutic and prognostic biomarker.

Dataset Information

METTL3-mediated m6A modification is required for cerebellar development.

Publications

METTL3-mediated m6A modification is required for cerebellar development.

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