组蛋白去甲基化酶JMJD2D在肝再生过程中调控肝细胞增殖的机制研究  

Mechanism of Histone Demethylase JMJD2D in Regulating Hepatocyte Proliferation During Liver Regeneration

作　　者：李诚 谢狄亚 LI Cheng;XIE Diya(Department of General Surgery,Fuzhou First General Hospital,Fuzhou,Fujian 350009,China)

机构地区：[1]福州市第一总医院普通外科,福建福州350009

出　　处：《中国医药指南》2025年第2期13-16,共4页Guide of China Medicine

基　　金：福建省自然科学基金项目(2022J011308)。

摘　　要：目的探讨组蛋白去甲基化酶JMJD2D在肝再生过程中对肝细胞增殖的调控机制。方法选取2022年5月至2024年4月接受部分肝切除的来自实验室的小鼠模型240只,采取随机数字表法分为对照组和研究组,各120只,对照组为野生型小鼠,研究组为JMJD2D敲除小鼠。对小鼠进行2/3肝切除术后,分别在多个时间点(24 h、38 h、48 h、168 h)收集肝脏组织样本,并进行RNA提取、蛋白质分析、免疫组织化学染色以及qPCR等实验。分析两组小鼠在肝脏体重恢复、肝功能指标(ALT、AST)及肝细胞增殖标志物(Brdu、Ki67)表达的差异。同时,利用转录组测序(RNA-seq)和染色质免疫沉淀测序(ChIP-seq)评估JMJD2D对细胞周期调控基因如FOXM1、CCNA2、CCNB1的影响。结果对照组的小鼠肝脏/体重比高于研究组(P<0.05)。对照组与研究组相比24 h、38 h、48 h及168 h的Ki67及Brdu表达水平均较高,对照组与研究组相比ALT及AST表达水平均较高,对照组与研究组相比FOXM1、CCNA2、CCNB1的基因表达均较高,对照组与研究组相比FOXM1、CCNA2、CCNB1的蛋白表达均较高(P<0.05)。结论JMJD2D的缺失会抑制肝细胞增殖和再生,提示其在肝再生治疗中的潜在应用价值。这为未来针对肝损伤修复和相关疾病治疗提供了新的靶点。Objective To investigate the regulatory mechanism of histone demethylase JMJD2D in hepatocyte proliferation during liver regeneration.Methods A total of 240 mice,selected from laboratory models between May 2022 and April 2024,underwent partial hepatectomy and were randomly assigned to control and study groups,each consisting of 120 mice.The control group comprised wild-type mice,while the study group included JMJD2D knockout mice.After performing a two-thirds hepatectomy,liver tissue samples were collected at various time points(24 hours,38 hours,48 hours,and 168 hours)and subjected to RNA extraction,protein analysis,immunohistochemical staining,and qPCR experiments.The differences in liver weight recovery,liver function indicators(ALT,AST),and the expression of hepatocyte proliferation markers(Brdu,Ki67)between the two groups of mice were analyzed.Additionally,the impact of JMJD2D on cell cycle regulatory genes such as FOXM1,CCNA2,and CCNB1 was assessed using transcriptome sequencing(RNA-seq)and chromatin immunoprecipitation sequencing(ChIP-seq).Results The ratio of liver weight to body weight in the control group mice was higher than that in the study group(P<0.05).Compared to the study group,the expression levels of Ki67 and Brdu at 24 hours,38 hours,48 hours,and 168 hours were higher in the control group.Similarly,the expression levels of ALT and AST were higher in the control group.The gene expression of FOXM1,CCNA2,and CCNB1 was also higher in the control group compared to the study group,and the protein expression of FOXM1,CCNA2,and CCNB1 was higher in the control group as well(P<0.05).Conclusions The absence of JMJD2D inhibits hepatocyte proliferation and liver regeneration,suggesting its potential as a therapeutic target in liver regeneration.This provides a novel approach for the repair of liver damage and treatment of related diseases.

关 键 词：组蛋白去甲基化酶 肝再生 肝细胞增殖 肝损伤修复 细胞周期 

分 类 号：R575[医药卫生—消化系统]