Diabetes Mellitus in Pregnancy Leads to Growth Restriction and Epigenetic Modification of the Srebf2 Gene in Rat Fetuses
Diabetes Mellitus in Pregnancy Leads to Growth Restriction and Epigenetic Modification of the Srebf2 Gene in Rat Fetuses
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DOI：
10.1161/hypertensionaha.117.10782
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发表时间：
2018-05-01
期刊：
影响因子：
8.3
通讯作者：
Dechend, Ralf
中科院分区：
文献类型：
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作者：
Golic, Michaela;Stojanovska, Violeta;Dechend, Ralf
糖尿病妊娠与后代代谢和神经系统疾病的风险增加相关，推测这是表观遗传学介导的。关于糖尿病妊娠胎儿中已经存在的表观遗传变化知之甚少。我们的目的是描述母体糖尿病后的围产期环境，并确定胎儿相关的表观遗传变化。我们重点关注转录因子Srebf2（sterol regulatory element binding transcriptionfactor 2），它是调节胆固醇代谢的主基因。我们测试了糖尿病妊娠是否诱导Srebf2启动子的表观遗传变化，以及它们是否在改变的Srebf2基因表达中变得明显。我们用转基因2型糖尿病大鼠模型（Tet29），其中胰岛素受体被多西环素诱导的RNA干扰敲低。Tet29和野生型对照大鼠在受孕前给予多西环素。只有Tet29多西环素母鼠出现高血糖、高胰岛素血症和高血脂。用实时定量逆转录聚合酶链反应和焦磷酸测序分析基因表达。对胎儿大脑进行免疫组织化学。糖尿病Tet29母鼠的胎仔在妊娠结束时出现高血糖和生长受限。与血糖正常母亲的胎儿相比，他们进一步显示肝脏和脑重量降低，同时海马中小胶质细胞活化减少。重要的是，糖尿病妊娠诱导了胎儿肝脏和大脑中Srebf2启动子的CpG超甲基化，这与Srebf2基因表达降低有关。总之，糖尿病和高脂血症妊娠诱导大鼠胎儿神经，代谢和表观遗传学的改变。Srebf2是一个潜在的候选人调解宫内环境驱动的表观遗传变化和后来的糖尿病后代的健康。
Diabetic pregnancy is correlated with increased risk of metabolic and neurological disorders in the offspring putatively mediated epigenetically. Little is known about epigenetic changes already present in fetuses of diabetic pregnancies. We aimed at characterizing the perinatal environment after preexisting maternal diabetes mellitus and at identifying relevant epigenetic changes in the fetus. We focused on the transcription factor Srebf2 (sterol regulatory element binding transcription factor 2), a master gene in regulation of cholesterol metabolism. We tested whether diabetic pregnancy induces epigenetic changes in the Srebf2 promoter and if they become manifest in altered Srebf2 gene expression. We worked with a transgenic rat model of type 2 diabetes mellitus (Tet29) in which the insulin receptor is knocked down by doxycycline-induced RNA interference. Doxycycline was administered preconceptionally to Tet29 and wild-type control rats. Only Tet29 doxycycline dams were hyperglycemic, hyperinsulinemic, and hyperlipidemic. Gene expression was analyzed with quantitative real-time reverse transcriptase polymerase chain reaction and CpG promoter methylation with pyrosequencing. Immunohistochemistry was performed on fetal brains. Fetuses from diabetic Tet29 dams were hyperglycemic and growth restricted at the end of pregnancy. They further displayed decreased liver and brain weight with concomitant decreased microglial activation in the hippocampus in comparison to fetuses of normoglycemic mothers. Importantly, diabetic pregnancy induced CpG hypermethylation of the Srebf2 promoter in the fetal liver and brain, which was associated with decreased Srebf2 gene expression. In conclusion, diabetic and hyperlipidemic pregnancy induces neurological, metabolic, and epigenetic alterations in the rat fetus. Srebf2 is a potential candidate mediating intrauterine environment-driven epigenetic changes and later diabetic offspring health.