实验性2型糖尿病小鼠肝脏组蛋白H3表观修饰的变化及其意义

doi:10.13481/j.1671-587x.20150417

吉林大学学报(医学版) ›› 2015, Vol. 41 ›› Issue (04): 756-762.doi: 10.13481/j.1671-587x.20150417

实验性2型糖尿病小鼠肝脏组蛋白H3表观修饰的变化及其意义

屠培培^1,2, 李晓丹¹, 马百成³, 张耀方⁴, 段会坤¹, 尼再中¹, 王海松¹, 姜苹哲¹, 李淼¹, 吴日¹, 李明刚¹

1. 南开大学生命科学学院分子生物学研究所生物活性材料教育部重点实验室, 天津 300071;
2. 安徽医科大学生命科学学院, 安徽合肥 230032;
3. 天津市儿童医院儿科研究所, 天津 300074;
4. 天津农学院基础科学学院, 天津 300384

收稿日期:2014-12-01 发布日期:2015-08-01
通讯作者: 李明刚,教授,博士研究生导师(Tel:022-23504582,E-mail:mgl@nankai.edu.cn) E-mail:mgl@nankai.edu.cn
作者简介:屠培培(1985-),女,安徽省蚌埠市人,理学博士,主要从事生物技术与新药开发方面的研究。
基金资助:
国家科技部863计划项目资助课题(2008AA02Z205);天津市科学技术委员会科技支撑重点计划项目资助课题(14ZCZDSY00013)

Changes and significance of hepatic histone H3 epigenetic modification in type 2 diabetic mice

TU Peipei^1,2, LI Xiaodan¹, MA Baicheng³, ZHANG Yaofang⁴, DUAN Huikun¹, NI Zaizhong¹, WANG Haisong¹, JIANG Pingzhe¹, LI Miao¹, WU Ri¹, LI Minggang¹

1. Key Laboratory for Bioactive Materials, Ministry of Education, Institute for Molecular Biology, College of Life Science, Nankai University, Tianjin 300071, China;
2. College of Life Science, Anhui Medical University, Hefei230032, China;
3. Tianjin Children's Hospital, Institute of Pediatrics, Tianjin 300074, China;
4. College of Basic Sciences, Tianjin Agricultural University, Tianjin 300384, China

Received:2014-12-01 Published:2015-08-01

摘要/Abstract

摘要：

目的: 研究肝脏组蛋白H3表观修饰的变化在2型糖尿病小鼠发病过程中的作用,探讨其临床意义。方法: 30只C57BL/6J小鼠分为正常组、高脂高糖组和糖尿病组,正常组和高脂高糖组小鼠分别给予正常饲料和高脂高糖饲料,糖尿病模型采用高脂高糖饲料联合注射链脲佐菌素(STZ)方法构建。采用HE染色、免疫印迹法、实时定量PCR和ChIP技术分别检测小鼠肝脏病理学变化、肝脏中总组蛋白H3的修饰状况及与糖代谢相关基因丙酮酸激酶(Pklr)、葡萄糖转运蛋白2(Glut2)、葡糖糖激酶(Gck)、过氧化物酶体增生物激活受体γ辅助活化因子 1(Ppargc1a)和胰岛素受体(Insr)的表达水平和基因启动子区组蛋白的修饰变化。结果: 糖尿病组小鼠肝脏病理学(HE染色)和组蛋白修饰模式均发生了明显变化。与正常组比较,高脂高糖组小鼠H3K23的乙酰化下降(P<0.01),H3K9Ac和H3K9Me2修饰水平上调(P<0.01),H3K4Me保持不变(P>0.05),糖代谢相关基因Pklr、Glut2和Gck的表达水平升高(P<0.01);糖尿病组小鼠H3K23Ac和H3K9Ac修饰水平下降(P<0.05或P<0.01),H3K9Me2和H3K4Me的修饰水平升高(P<0.01),糖代谢相关基因Pklr、Glut2、Gck、Ppargc1a和Insr表达水平明显下调(P<0.05或P<0.01)。Pklr、Glut2启动子区H3K23Ac、H3K9Ac、H3K9Me2和H3K4Me修饰水平变化与基因的表达水平变化相吻合。结论: 肝脏组蛋白表观修饰变化可能参与了2型糖尿病的发生发展。

关键词: 2型糖尿病, 表观遗传学, 组蛋白H3, 丙酮酸激酶, 葡萄糖转运蛋白2

Abstract:

Objective To study the role of liver total histone epigenetic modification changes in the development of type 2 diabetes mellitus in the mice,and to explore its clinical significance. Methods Thirty C57BL/6J mice were divided into normal group,high-fat high-sucrose (HFS) group and type 2 diabetes mellitus (T2DM) group.The mice in normal and HFS groups were given regular diet and HFS diet,respectively,while type 2 diabetic mice were induced by HFS diet plus streptozotocin (STZ).HE staining,Western blotting,Quantitative PCR and ChIP assay were used to analyze the pathological changes of liver tissue of the mice,total histone H3 modification,the expression levels of glucose metabolism-related genes and histone H3 modification in gene promoter. Results The liver pathology after HE staining and modification patterns of histone of the mice in T2DM group were significantly different from other groups.Compared with normal group,the H3K23 acetylation of the mice in HFS group was decreased (P<0.01),the modification levels of H3K9Ac and H3K9Me2 were increased (P<0.01),the level of H3K4Me had no change (P>0.05),and the expression levels of glucose metabolism-related genes Pklr,Glut2 and Gck were increased (P<0.01). Compared with normal group,the modification levels of H3K23Ac (P<0.01) and H3K9Ac (P<0.05) in T2DM group were decreased, the modification levels of H3K9Me2 and H3K4Me were increased (P<0.01),and the expression levels of glucose metabolism-related genes Pklr,Glut2,Gck,Ppargc1a and Insr were decreased (P<0.05 or P<0.01).Moreover,the changes of H3K23Ac,H3K9Ac,H3K9Me2 and H3K4Me modification in gene promoter of Glut2 and Pklr showed consistent with its expression levels. Conclusion The epigenetic modification changes of liver histone might participate in the occurrence and development of type 2 diabetes mellitus.

Key words: type 2 diabetes mellitus, epigenetics, histone H3, pyruvate kinase, glucose transporter protein 2

中图分类号:

R589.1

屠培培, 李晓丹, 马百成, 张耀方, 段会坤, 尼再中, 王海松, 姜苹哲, 李淼, 吴日, 李明刚. 实验性2型糖尿病小鼠肝脏组蛋白H3表观修饰的变化及其意义[J]. 吉林大学学报(医学版), 2015, 41(04): 756-762.

TU Peipei, LI Xiaodan, MA Baicheng, ZHANG Yaofang, DUAN Huikun, NI Zaizhong, WANG Haisong, JIANG Pingzhe, LI Miao, WU Ri, LI Minggang. Changes and significance of hepatic histone H3 epigenetic modification in type 2 diabetic mice[J]. Journal of Jilin University Medicine Edition, 2015, 41(04): 756-762.

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实验性2型糖尿病小鼠肝脏组蛋白H3表观修饰的变化及其意义

Changes and significance of hepatic histone H3 epigenetic modification in type 2 diabetic mice

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