Dataset Information

Methyltransferase 3 Mediated miRNA m6A Methylation Promotes Stress Granule Formation in the Early Stage of Acute Ischemic Stroke.

ABSTRACT: The modification of methyltransferase-like (METTL) enzymes plays important roles in various cellular responses by regulating microRNA expression. However, how m6A modification is involved in stress granule (SG) formation in the early stage of acute ischemic stroke by affecting the biogenesis processing of microRNAs remains unclear. Here, we established a middle cerebral artery occlusion (MCAO) model in rats and an oxygen-glucose deprivation/reperfusion (OGD/R) model in primary cortical neurons and PC12 cells to explore the potential mechanism between m6A modification and SG formation. The in vivo results showed that the level of infarction and apoptosis increased while SG formation decreased significantly within the ischemic cortex with improved reperfusion time after 2 h of ischemia. Consistent with the in vivo data, an inverse association between the apoptosis level and SG formation was observed in PC12 cells during the reperfusion period after 6 h of OGD stimulation. Both in vivo and in vitro results showed that the expression of METTL3 protein, m6A and miR-335 was significantly decreased with the reperfusion period. Overexpression of the METTL3 and METTL3 gene-knockdown in PC12 cells were achieved via plasmid transfection and CRISPR-Cas9 technology, respectively. Overexpression or knockdown of METTL3 in oxygen-glucose deprivation of PC12 cells resulted in functional maturation of miR-335, SG formation and apoptosis levels. In addition, we found that miR-335 enhanced SG formation through degradation of the mRNA of the eukaryotic translation termination factor (Erf1). In conclusion, we found that METTL3-mediated m6A methylation increases the maturation of miR-335, which promotes SG formation and reduces the apoptosis level of injury neurons and cells, and provides a potential therapeutic strategy for AIS.

SUBMITTER: Si W

PROVIDER: S-EPMC7289951 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Methyltransferase 3 Mediated miRNA m6A Methylation Promotes Stress Granule Formation in the Early Stage of Acute Ischemic Stroke.

Si Wenwen W Li Yi Y Ye Shanyu S Li Zhen Z Liu Yangping Y Kuang Weihong W Chen Dongfeng D Zhu Meiling M

Frontiers in molecular neuroscience 20200605

The modification of methyltransferase-like (METTL) enzymes plays important roles in various cellular responses by regulating microRNA expression. However, how m6A modification is involved in stress granule (SG) formation in the early stage of acute ischemic stroke by affecting the biogenesis processing of microRNAs remains unclear. Here, we established a middle cerebral artery occlusion (MCAO) model in rats and an oxygen-glucose deprivation/reperfusion (OGD/R) model in primary cortical neurons a ...[more]

PMID: 32581712

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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

Methyltransferase 3 Mediated miRNA m6A Methylation Promotes Stress Granule Formation in the Early Stage of Acute Ischemic Stroke.

Publications

Methyltransferase 3 Mediated miRNA m6A Methylation Promotes Stress Granule Formation in the Early Stage of Acute Ischemic Stroke.

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