低叶酸和维甲酸诱导神经管畸形小鼠模型胎脑的转录物组学分析

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中文摘要：神经管畸形(neural tube defects，NTDs)是一类中枢神经系统相关的重大出生缺陷型疾病。随着孕龄期妇女叶酸增补政策的推广，其发病率逐年下降致临床标本不易获取，因此，建立可靠的动物模型来研究NTDs的致病机制尤为重要。本研究分别通过低叶酸联合甲氨蝶呤(methotrexate，MTX)建立的诱导NTDs小鼠模型和维甲酸(retinoic acid，RA)诱导建立的NTDs小鼠模型，对NTDs胎鼠脑组织进行转录物组测序(transcriptome sequencing，RNA-seq)并分析差异表达谱，最后，通过实时荧光定量 PCR(real-time quantitative polymerase chain reaction，RT-qPCR)进行结果验证。结果显示，低叶酸联合MTX诱导的胎鼠NTDs发生率为21。7％;RA诱导的胎鼠出现了强烈的致畸现象，畸形率为73。2％。相比正常胎鼠，低叶酸联合MTX诱导的NTDs小鼠组筛选出1 443个差异表达基因(differentially expression genes，DEGs);RA 诱导 NTDs 小鼠组筛选出 3 070 个 DEGs。对DEGs进行生物信息学分析，GO富集显示，上调基因主要参与前后轴发育、区域化和模式分化过程等生物学过程;KEGG富集显示，上调基因与心肌收缩、心肌病、神经活性配体-受体相互作用等信号通路相关。对2种模型鼠的DEGs进行Veen交集分析，结果显示，共有132个DEGs在2组模型中显著上调，其中包括Hox基因家族。通过RT-qPCR进行验证，发现与RNA-seq的结果一致。本研究对2种NTDs小鼠胎脑进行RNA-seq和差异表达谱分析，发现Hox的异常表达可能导致了NTDs的发生，为后续发病机制的研究提供了探索与思考。

外文标题：Transcriptomic Analysis of Fetal Brain Induced by Low Folate and Retinoic Acid in NTDs Mouse Model

外文摘要：Neural tube defects(NTDs)are a class of major birth defects associated with the central nervous system.With the promotion of folic acid supplementation policy in pregnant women,the inci-dence of folic acid is decreasing year by year,which makes it difficult to obtain clinical specimens.Therefore,it is particularly important to establish reliable animal models to study the pathogenesis of NTDs.In this study,the NTDs mouse model induced by low folate combined with methotrexate(MTX)and the NTDs mouse model induced by retinoic acid(RA)were respectively established.transcriptome sequencing(RNA-seq)was performed on the brain tissue of NTDs fetal mice and differential expression profiles were analyzed.The results were verified by real-time quantitative polymerase chain reaction(RT-qPCR).The results showed that the incidence of NTDs induced by low folate combined with MTX was 21.7％.RA-induced fetal mice showed strong teratogenicity,with a deformity rate of 73.2％.Compared with normal fetal mice,1 443 differentially expressed genes(DEGs)were screened in NTDs mice in-duced by low folate combined with MTX.Totally 3 070 DEGs were screened in RA-induced NTDs mice.Bioinformatics analysis of DEGs showed that the up-regulated genes were mainly involved in the antero-posterior axis development,regionalization,pattern differentiation and other biological processes.KEGG enrichment showed that up-regulated genes were associated with myocardial contraction,cardiomyopathy,and neuroactive ligand-receptor interactions.Veen intersection analysis of DEGs in the two models showed that a total of 132 DEGs were significantly up-regulated in both sets of models,including the Hox gene family.The results were verified by RT-qPCR and found to be consistent with those of RNA-seq.In this study,RNA-seq and differential expression profiles were analyzed in the fetal brains of two NTDs mice,and it was found that the abnormal expression of Hox might lead to the occurrence of NTDs,which provided exploration and reflection for the subsequent pathogenesis research.

外文关键词：

neural tube defects(NTD)transcriptome sequencingfolic acid(FA)retinoic acid(RA)homeobox gene

作者：

曹志华、谷小龙、解琪、李建婷、方爱莉、刘志贞

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作者单位：

山西医科大学基础医学院生物化学与分子生物学教研室出生缺陷与细胞再生山西省重点实验室,太原 030001

煤炭环境致病与防治教育部重点实验室,太原 030001

山西医科大学第三医院(山西白求恩医院山西医学科学院同济山西医院)麻醉科,太原 030000

关键词：

神经管畸形转录物组测序叶酸维甲酸同源盒基因

基金：

国家自然科学基金国家自然科学基金山西省基础研究计划山西省基础研究计划山西医科大学博士启动基金山西医科大学博士启动基金

项目编号：

U23A2042082201841202203021212369202203021221245SD2209XD2116

出版年：

2024

DOI：

10.13865/j.cnki.cjbmb.2024.04.1011

中国生物化学与分子生物学报

中国生物化学与分子生物学会北京大学

中国生物化学与分子生物学报

CSTPCD北大核心

影响因子：0.617

ISSN：1007-7626

年,卷(期)：2024.40(5)

参考文献量28