Dataset Information

Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation.

ABSTRACT: N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here, we show that m6A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m6A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m6A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m6A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m6A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m6A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m6A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.

SUBMITTER: Yoon KJ

PROVIDER: S-EPMC5679435 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Publications

Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation.

Yoon Ki-Jun KJ Ringeling Francisca Rojas FR Vissers Caroline C Jacob Fadi F Pokrass Michael M Jimenez-Cyrus Dennisse D Su Yijing Y Kim Nam-Shik NS Zhu Yunhua Y Zheng Lily L Kim Sunghan S Wang Xinyuan X Doré Louis C LC Jin Peng P Regot Sergi S Zhuang Xiaoxi X Canzar Stefan S He Chuan C Ming Guo-Li GL Song Hongjun H

Cell 20170928 4

N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here, we show that m6A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m6A depletion by Mettl3 knockdown also leads to a prolonged cell cy ...[more]

PMID: 28965759

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Project description:MOTIVATION:As the most abundant mammalian mRNA methylation, N6-methyladenosine (m6A) exists in >25% of human mRNAs and is involved in regulating many different aspects of mRNA metabolism, stem cell differentiation and diseases like cancer. However, our current knowledge about dynamic changes of m6A levels and how the change of m6A levels for a specific gene can play a role in certain biological processes like stem cell differentiation and diseases like cancer is largely elusive. RESULTS:To address this, we propose in this paper FunDMDeep-m6A a novel pipeline for identifying context-specific (e.g. disease versus normal, differentiated cells versus stem cells or gene knockdown cells versus wild-type cells) m6A-mediated functional genes. FunDMDeep-m6A includes, at the first step, DMDeep-m6A a novel method based on a deep learning model and a statistical test for identifying differential m6A methylation (DmM) sites from MeRIP-Seq data at a single-base resolution. FunDMDeep-m6A then identifies and prioritizes functional DmM genes (FDmMGenes) by combing the DmM genes (DmMGenes) with differential expression analysis using a network-based method. This proposed network method includes a novel m6A-signaling bridge (MSB) score to quantify the functional significance of DmMGenes by assessing functional interaction of DmMGenes with their signaling pathways using a heat diffusion process in protein-protein interaction (PPI) networks. The test results on 4 context-specific MeRIP-Seq datasets showed that FunDMDeep-m6A can identify more context-specific and functionally significant FDmMGenes than m6A-Driver. The functional enrichment analysis of these genes revealed that m6A targets key genes of many important context-related biological processes including embryonic development, stem cell differentiation, transcription, translation, cell death, cell proliferation and cancer-related pathways. These results demonstrate the power of FunDMDeep-m6A for elucidating m6A regulatory functions and its roles in biological processes and diseases. AVAILABILITY AND IMPLEMENTATION:The R-package for DMDeep-m6A is freely available from https://github.com/NWPU-903PR/DMDeepm6A1.0. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

Dataset Information

Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation.

Publications

Temporal Control of Mammalian Cortical Neurogenesis by m<sup>6</sup>A Methylation.

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