颞叶癫痫microRNA基因甲基化模式分析及机制探究

Genome-wide DNA methylation patterns of miRNAs in temporal lobe epilepsy patients and its underlying mechanism

摘要:

目的 重注释甲基化数据并构建microRNA（miRNA）基因甲基化谱，探究差异甲基化miRNA在颞叶癫痫（TLE）发生发展及耐药机制中的作用。方法 收集TLE患者以及健康对照外周血，提取 DNA进行全基因组DNA甲基化检测。将甲基化数据重注释至miRNA基因，统计分析筛选病例组与对照组以及临床亚组之间的差异甲基化miRNA，运用生物信息学方法对差异甲基化miRNA功能分析。结果 TLE和对照组间有82个miRNA基因甲基化存在差异（FDR<5%），其中甲基化升高的70个。临床亚组间也存在差异甲基化miRNA基因（P<0.01）。差异甲基化miRNA基因参与MAPK信号通路、神经营养信号通路等多条生物学通路。结论 TLE患者外周血miRNA基因组甲基化存在异常，以甲基化程度升高为主。差异甲基化miRNA基因参与多条生物学通路，可能在TLE发病及耐药机制中起到重要作用。

Abstract:

Objective To explore the role of differentially methylated microRNAs (miRNAs) in the development and progression of temporal lobe epilepsy (TLE) and its drug resistance by reannotating the data of DNA methylation and constructing DNA methylation profiles for miRNAs.Methods Peripheral blood samples were collected from TLE patients and healthy controls for DNA extraction. Genome-wide DNA methylation was measured and reannotated to miRNAs. Statistical analysis was performed to identify miRNAs with differentially methylated 5'-C-phosphate-G-3' (CpG) between TLE patients and healthy controls and between different clinical subgroups. Bioinformatics analysis was used to analyze the functions of the aberrantly methylated miRNAs.Results In total, 82 miRNA CpG sites were found to be differentially methylated between TLE patients and controls (false discovery rate <5%), with 70 (85%) of them hypermethylated. There was also a set of differentially methylated miRNAs between different clinical subgroups (P<0.01). Pathway analysis showed that differentially methylated miRNAs were involved in mitogen-activated protein kinase signaling pathway, neurotrophin signaling pathway, and other biological pathways.Conclusions MiRNAs display altered methylation profiles in peripheral blood from TLE patients, and most of them are hypermethylated. Aberrantly methylated miRNAs are related to multiple biological signaling pathways, which might be involved in the pathogenesis and drug resistance of TLE.