N(1)-Methyladenosine modification of mRNA regulates neuronal gene expression and oxygen glucose deprivation/reoxygenation induction.
N(1)-Methyladenosine modification of mRNA regulates neuronal gene expression and oxygen glucose deprivation/reoxygenation induction.
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DOI：
10.1038/s41420-023-01458-2
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发表时间：
2023-05-12
影响因子：
7
通讯作者：
Zhou, Hengxing
中科院分区：
文献类型：
--
作者：
Qi, Zhangyang;Zhang, Chi;Jian, Huan;Hou, Mengfan;Lou, Yongfu;Kang, Yi;Wang, Wei;Lv, Yigang;Shang, Shenghui;Wang, Chaoyu;Li, Xueying;Feng, Shiqing;Zhou, Hengxing
N1-甲基腺苷（m1A）是一种丰富的转录修饰物，在调节mRNA结构和翻译效率方面发挥重要作用，并在应激条件下受到动态调节。然而，原代神经元和氧葡萄糖剥夺/复氧（OGD/R）诱导的mRNA m1A修饰的特点和功能尚不清楚。我们首先构建了小鼠皮层神经元OGD/R模型，然后使用甲基化RNA免疫沉淀（MeRIP）和测序技术来证明m1A修饰在神经元mRNA中是丰富的，并在OGD/R诱导过程中动态调节。我们的研究表明，Trmt 10 c，Alkbh 3和Ythdf 3可能是在OGD/R诱导的神经元中的m1A调节酶。在OGD/R诱导过程中，m1A修饰的水平和模式发生显著变化，差异甲基化与神经系统密切相关。我们的研究结果表明，皮质神经元中的m1A峰聚集在5'和3'非翻译区。m1A修饰可以调控基因表达，不同区域的峰对基因表达的影响不同。通过分析m1A-seq和RNA-seq数据，我们发现差异甲基化m1A峰与基因表达之间存在正相关性。通过qRT-PCR和MeRIP-RT-PCR验证相关性。此外，我们从基因表达综合（GEO）数据库中选择帕金森病（PD）和阿尔茨海默病（AD）患者的人体组织样本，分别分析所选的差异表达基因（DEG）和差异甲基化修饰调节酶，发现相似的差异表达结果。我们强调了m1A修饰和OGD/R诱导后神经元凋亡之间的潜在关系。此外，通过定位小鼠皮层神经元和OGD/R诱导的修饰特征，揭示了m1A修饰在OGD/R和基因表达调控中的重要作用，为神经损伤的研究提供了新的思路。
N1-Methyladenosine (m1A) is an abundant modification of transcripts, plays important roles in regulating mRNA structure and translation efficiency, and is dynamically regulated under stress. However, the characteristics and functions of mRNA m1A modification in primary neurons and oxygen glucose deprivation/reoxygenation (OGD/R) induced remain unclear. We first constructed a mouse cortical neuron OGD/R model and then used methylated RNA immunoprecipitation (MeRIP) and sequencing technology to demonstrate that m1A modification is abundant in neuron mRNAs and dynamically regulated during OGD/R induction. Our study suggests that Trmt10c, Alkbh3, and Ythdf3 may be m1A-regulating enzymes in neurons during OGD/R induction. The level and pattern of m1A modification change significantly during OGD/R induction, and differential methylation is closely associated with the nervous system. Our findings show that m1A peaks in cortical neurons aggregate at both the 5’ and 3’ untranslated regions. m1A modification can regulate gene expression, and peaks in different regions have different effects on gene expression. By analysing m1A-seq and RNA-seq data, we show a positive correlation between differentially methylated m1A peaks and gene expression. The correlation was verified by using qRT-PCR and MeRIP-RT-PCR. Moreover, we selected human tissue samples from Parkinson’s disease (PD) and Alzheimer’s disease (AD) patients from the Gene Expression Comprehensive (GEO) database to analyse the selected differentially expressed genes (DEGs) and differential methylation modification regulatory enzymes, respectively, and found similar differential expression results. We highlight the potential relationship between m1A modification and neuronal apoptosis following OGD/R induction. Furthermore, by mapping mouse cortical neurons and OGD/R-induced modification characteristics, we reveal the important role of m1A modification in OGD/R and gene expression regulation, providing new ideas for research on neurological damage.
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作者：
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