基于转录组和DNA甲基化组的白鲜碱致小鼠肝损伤的性别差异研究

Gender differences in dictamnin-induced liver injury in mice based on transcriptome and DNA methylation

背景白鲜碱是中药白鲜皮的主要成分,具有肝毒性,可诱导肝损伤。临床发现,白鲜碱致肝损伤的发病率女性高于男性。目的绘制DNA甲基化组及转录组图谱,探索白鲜碱致肝损伤性别差异的调控机制。方法构建白鲜碱诱导的肝损伤雌性和雄性小鼠模型,对小鼠肝进行转录组测序(RNA-sequencing,RNA-seq)和全基因组重亚硫酸盐测序(whole genome bisulfite sequencing,WGBS),探究雌性与雄性小鼠肝经白鲜碱诱导损伤后的差异信号通路和DNA甲基化调控的变化。结果白鲜碱会额外激活雌性小鼠肝的外源性药物分解代谢及脂肪酸代谢,并导致雌性小鼠肝全局性的DNA高甲基化。行使外源性药物分解代谢、脂肪酸代谢的核心基因Cyp2d9,Cyp2c67因基因体区域发生DNA高甲基化(diff.Methy=0.326,diff.Methy=0.355)而被促进表达(log2FC=4.247,P<0.001;log2FC=3.331,P<0.001)。结论白鲜碱导致雌性小鼠肝发生全局性的DNA高甲基化,从而上调肝分解代谢外源性药物、脂肪酸等功能,可能是白鲜碱导致雌性小鼠更易发肝损伤的原因。

Background Dictamnine is the main component of cortex dictamni and has hepatotoxicity,and the incidence of liver injury induced by dictamnine in female is higher than that in male.Objective To explore the mechanism of DNA methylation and transcriptional regulation of dictamnine-induced liver injury in different genders by drawing DNA methylation and transcriptome profiles.Methods The male and female mouse models of dictamnine-induced liver injury were constructed.The transcriptome sequencing(RNA-seq)and whole genome bisulfite sequencing(WGBS)of mouse liver were performed to explore the changes of differential signaling pathways and DNA methylation regulation after dictamnine-induced liver injury in male and female mice.Results Dictamnine additionally activated exogenous drug catabolism and fatty acid metabolism in the liver of female mice,while caused global DNA hypermethylation in the liver of female mice.The core genes Cyp2d9 and Cyp2c67 that exercised exogenous drug catabolism and fatty acid metabolism were promoted(log2FC=4.247,P<0.001;log2FC=3.331,P<0.001)by DNA hypermethylation(diff.Methy=0.326,diff.Methy=0.355)in the gene body region.Conclusion Dictamnine causes global DNA hypermethylation in the liver of female mice,which up-regulates the liver to perform exogenous drug catabolism,fatty acid metabolism and other functions,which may be the reason why dictamnine causes more liver injury in female mice.