Dataset Information

Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA m⁶A-methylation of Npdc1 and Cend1.

ABSTRACT: N ⁶-methyladenosine (m⁶A) is emerging as a vital factor regulating neural differentiation. Here, we report that deficiency of Arhgef2, a novel cause of a neurodevelopmental disorder we identified recently, impairs neurogenesis, neurite outgrowth, and synaptic formation by regulating m⁶A methylation. Arhgef2 knockout decreases expression of Mettl14 and total m⁶A level significantly in the cerebral cortex. m⁶A sequencing reveals that loss of Arhgef2 reduces m⁶A methylation of 1,622 mRNAs, including Npdc1 and Cend1, which are both strongly associated with cell cycle exit and terminal neural differentiation. Arhgef2 deficiency decreases m⁶A methylations of the Npdc1 and Cend1 mRNAs via down-regulation of Mettl14, and thereby inhibits the translation of Npdc1 and nuclear export of Cend1 mRNAs. Overexpression of Mettl14, Npdc1, and Cend1 rescue the abnormal phenotypes in Arhgef2 knockout mice, respectively. Our study provides a critical insight into a mechanism by which defective Arhgef2 mediates m⁶A-tagged target mRNAs to impair neural differentiation.

SUBMITTER: Zhou P

PROVIDER: S-EPMC8185223 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA m6A-methylation of Npdc1 and Cend1.

Zhou Pei P Qi Yifei Y Fang Xiang X Yang Miaomiao M Zheng Shuxin S Liao Caihua C Qin Fengying F Liu Lili L Li Hong H Li Yan Y Ravindran Ethiraj E Sun Chuanbo C Wei Xinshu X Wang Wen W Fang Liang L Han Dingding D Peng Changgeng C Chen Wei W Li Na N Kaindl Angela M AM Hu Hao H

iScience 20210524 6

N 6-methyladenosine (m6A) is emerging as a vital factor regulating neural differentiation. Here, we report that deficiency of Arhgef2, a novel cause of a neurodevelopmental disorder we identified recently, impairs neurogenesis, neurite outgrowth, and synaptic formation by regulating m6A methylation. Arhgef2 knockout decreases expression of Mettl14 and total m6A level significantly in the cerebral cortex. m6A seque ...[more]

PMID: 34142067

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Project description:BackgroundN6-Methyladenosine (m6A) modification has been implicated in many biological processes. It is important for the regulation of messenger RNA (mRNA) stability, splicing, and translation. However, its role in cancer has not been studied in detail. Here we investigated the biological role and underlying mechanism of m6A modification in hepatoblastoma (HB).MethodsWe used Reverse transcription quantitative real-time PCR (RT-qPCR) and Western blotting to determine the expression of m6A related factors. And we clarified the effects of these factors on HB cells using cell proliferation assay, colony formation, apoptotic assay. Then we investigated of methyltransferase-like 13 (METTL3) and its correlation with clinicopathological features and used xenograft experiment to check METTL3 effect in vivo. m6A-Seq was used to profiled m6A transcriptome-wide in hepatoblastoma tumor tissue and normal tissue. Finally, methylated RNA immunoprecipitation (MeRIP) assay, RNA remaining assay to perform the regulator mechanism of MEETL3 on the target CTNNB1 in HB.ResultsIn this research, we discovered that m6A modifications are increased in hepatoblastoma, and METTL3 is the main factor involved with aberrant m6A modification. We also profiled m6A across the whole transcriptome in hepatoblastoma tumor tissues and normal tissues. Our findings suggest that m6A is highly expressed in hepatoblastoma tumors. Also, m6A is enriched not only around the stop codon, but also around the coding sequence (CDS) region. Gene ontology analysis indicates that m6A mRNA methylation contributes significantly to regulate the Wnt/β-catenin pathway. Reduced m6A methylation can lead to a decrease in expression and stability of the CTNNB1.ConclusionOverall our findings suggest enhanced m6A mRNA methylation as an oncogenic mechanism in hepatoblastoma, METTL3 is significantly up-regulated in HB and promotes HB development. And identify CTNNB1 as a regulator of METTL3 guided m6A modification in HB.

Dataset Information

Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA m⁶A-methylation of Npdc1 and Cend1.

Publications

Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA m<sup>6</sup>A-methylation of Npdc1 and Cend1.

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