组蛋白去甲基转移酶Jmjd3通过表观修饰调控先兆子痫辅助性T细胞1/2失衡的作用及机制探究  

Function and mechanism of histone demethytransferase Jmjd3 mediated regulation of Th1/Th2 balance through epigenetic modification in pre-eclampsia

作　　者：徐亚辉[1] 刘侃[1] 闫珺[1] 王焕萍[1] 武海英[1] Xu Yahui;Liu Kan;Yan Jun;Wang Huanping;Wu Haiying(Department of Obstetrics,Henan Provincial People′s Hospital,Zhengzhou 450003,China)

机构地区：[1]河南省人民医院产科,郑州450003

出　　处：《中华病理学杂志》2020年第10期1041-1045,共5页Chinese Journal of Pathology

摘　　要：目的观察组蛋白去甲基转移酶Jmjd3在先兆子痫患者中的表达水平,探讨其介导的表观修饰调控先兆子痫患者的Th1/Th2失衡的可能作用机制。方法收集2018年1月至2019年6月河南省人民医院产科23例初产妇先兆子痫住院患者作为研究组,选取同期在该院接受分娩的19名正常孕妇作为对照组。采用逆转录即时荧光定量PCR(RT-PCR)检测先兆子痫患者和正常孕妇外周血单个核细胞(peripheral blood monocyte cells,PBMC)中组蛋白去甲基转移酶Jmjd3 mRNA水平,酶联免疫吸附试验(ELISA)检测两组孕妇外周血清γ干扰素(IFN-γ)和白细胞介素(IL)-4的含量;RT-PCR检测先兆子痫和对照组小鼠脾脏中Jmjd3、Tbx21和Cxcr3的mRNA水平;免疫磁珠法分选出对照组和先兆子痫小鼠脾脏初始CD4^+T细胞,Western blot检测其H3K27me1和H3K27me3水平;染色质免疫共沉淀(ChIP)分析先兆子痫小鼠脾脏中H3K27me3去甲基化修饰水平。结果与正常孕妇相比较,先兆子痫患者PBMC中Jmjd3 mRNA水平明显升高,血清中IFN-γ水平显著升高,IL-4水平明显降低(P<0.01);与正常对照组小鼠相比较,先兆子痫小鼠脾脏Jmjd3 mRNA水平明显升高,且在先兆子痫小鼠中,Tbx21和Cxcr3的表达均明显升高(P<0.01);先兆子痫小鼠初始CD4^+T细胞H3K27me3水平明显降低(P<0.05),H3K27me1则没有变化;ChIP分析表明,与对照组小鼠相比较,先兆子痫组小鼠CD4^+T细胞H3K27me3在Ifng启动子区的募集明显降低,而在Il4启动子区的募集明显升高(P<0.01)。结论不论是在先兆子痫患者还是小鼠中,组蛋白去甲基转移酶Jmjd3相对表达水平明显上调,进而诱导Ifng启动子区的H3K27me3发生去甲基化修饰,促进初始CD4^+T细胞向Th1细胞分化发育,导致Th1/Th2失衡,这可能是促进先兆子痫发生发展的重要原因之一。Objective To observe the expression level of histone demethyltransferase Jmjd3 in patients with pre-eclampsia(PE),and to investigate the possible mechanism of its epigenetic modification in regulating Th1/Th2 imbalance in PE patients.Methods The mRNA levels of histone demethyltransferase Jmjd3 from peripheral blood mononuclear cells(PBMC)of PE patients and normal pregnant women were detected by RT-PCR.Peripheral serum IFN-γand IL-4 were detected by ELISA.RT-PCR was used to detect the mRNA levels of Jmjd3,Tbx21 and Cxcr3 in the spleen of PE and control mice.Immunomagnetic beads were used to sort out the initial CD4^+T cells in the spleen of control and PE mice.Western blot was used to detect H3K27me1 and H3K27me3 levels.ChIP analysis was used for H3K27me3 demethylation modification in spleens of PE mice.Results Compared with normal pregnant women,the mRNA level of Jmjd3 in PBMC of PE patients was significantly increased,the level of IFN-γin serum was significantly increased,and the level of IL-4 was significantly reduced(P<0.01).Compared with normal control mice,the mRNA level of Jmjd3 in the spleen of PE mice was significantly increased,and the expression of Tbx21 and Cxcr3 was significantly increased in PE mice(P<0.01);the H3K27me3 level of CD4^+T cells in PE mice was significantly reduced(P<0.05),but H3K27me1 was not changed.ChIP analysis showed that CD4^+T cells H3K27me3 in PE group mice were in the Ifng promoter region,compared with control mice.Recruitment was significantly reduced,while recruitment in the promoter region of Il4 was significantly increased(P<0.01).Conclusions In both PE patients and mice with PE model,the relative expression level of histone demethyltransferase Jmjd3 is significantly up-regulated,which further induces the demethylation of H3K27me3 in the Ifng promoter region and promotes the initial CD4^+T cells to Th1 cell differentiation and development,leading to an imbalance of Th1/Th2,which may be one of the important reasons for the development of preeclampsia.

关 键 词：先兆子痫 表观修饰 组蛋白去甲基转移酶Jmjd3 辅助性T细胞 

分 类 号：R714.244[医药卫生—妇产科学]