Biol Reprod:母亲糖尿病能削弱卵母细胞印迹基因的甲基化

科研人员首次证明了没有得到良好控制的母亲糖尿病能对母亲印迹基因Peg3的甲基化产生不良影响，这对后代发育受到损害有贡献。

此前的研究已经表明，糖尿病母亲的后代表现出了更高的畸形和死胎的发生率，即便是把一个单细胞胚胎从糖尿病母亲移植到非糖尿病母亲体内的时候也是如此。糖尿病母亲的卵母细胞倾向于表现出葡萄糖代谢减少，卵丘细胞和卵母细胞之间的通信被削弱，线粒体失灵，以及排卵率下降，所有这些都可以追溯到胚胎基因表达的减少。

中国科学院的Qing-Yuan Sun 和 Zhao-Jia Ge提出了一种假说，即基因表达减少的原因是在卵子发生和卵母细胞期间DNA的再甲基化被干扰。该研究组培育并研究了3个不同的小鼠种群，其中一个种群自发出现糖尿病，一个种群的糖尿病是由注射STZ引起的，而另一个种群没有糖尿病。在第15天交配之后，有糖尿病的小鼠的怀孕率减少（大约74%，非糖尿病小鼠是100%），而且胚胎死亡率增加（大约16%，非糖尿病小鼠是0%），这符合此前的报道。

这个研究组把重点放在了一个父亲甲基化基因（H19）和两个母亲甲基化基因（Peg3和Snrpn）的甲基化模式上，他们发现这些基因在注射STZ后的35天内都没有表现出甲基化削弱；然而，胚胎发育和后代数量已经在第15天受到了影响。在第35天，Peg3 的甲基化显著减少，这两种糖尿病小鼠的未甲基化的卵母细胞率比对照组高了将近22%。H19仍然未受影响，对Snrpn的影响不显著。

对于糖尿病母亲的雌性后代，它们的卵母细胞看上去没有任何甲基化异常；然而，由于难以产生在第15天以后受孕产生的后代，很难确定这些雌性是否受到了类似的影响。

与糖尿病相关的拓展阅读：

• Diabetologia:血钾低的高血压患者易患糖尿病
• JBJS：糖尿病患者全膝关节置换术后并无过高感染风险
• Health Psychol：临床确诊糖尿病者抑郁风险增加
• ABEM：抑郁治疗可改善糖尿病人体力活动
• PDS：抗抑郁药降低糖尿病人服药依从性
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DOI 10.1095/biolreprod.112.105981
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Maternal diabetes causes alterations of DNA methylation statuses of some imprinted genes in murine oocytes

Ge ZJ, Liang XW, Guo L, Liang QX, Luo SM, Wang YP, Wei YC, Han ZM, Schatten H, Suna QY.

March 20, 2013 in Diabetes For the first time, researchers have shown that poorly controlled maternal diabetes has an adverse effect on methylation of the maternal imprinting gene Peg3, contributing to impaired development in offspring. google_protectAndRun("render_ads.js::google_render_ad", google_handleError, google_render_ad);Ads by GoogleDNA Methylation Products - MethylEasy? DNA Bisulfite Kit reduces DNA loss by over 90%. - www.geneticsignatures.comBrain Training Games - Improve memory and attention with scientific brain games. Free Trial - www.lumosity.com Previous studies have revealed that offspring of diabetic mothers display a higher incidence of malformations and fetal death, even when a one-cell embryo is transplanted from a diabetic to a non-diabetic mother. Diabetic mothers' oocytes tend to exhibit reduced glucose metabolism, compromised communication between cumulus cells and oocytes, mitochondrial malfunction, and a decreased ovulation rate, all of which can be traced back to reduced gene expression in the embryos. Qing-Yuan Sun and Zhao-Jia Ge of the Chinese Academy of Sciences hypothesized that the reduced gene expression results from disturbed DNA re-methylation during oogenesis and oocyte maturation. The team bred and examined three different mouse populations: one with spontaneously occurring diabetes, one with diabetes induced by STZ injection, and one without diabetes. After mating on Day 15, the diabetic mice presented with reduced pregnancy rates (approx. 74% vs. 100% in non-diabetic mice) and increased embryo death rates (approx. 16% vs. 0%), consistent with previous reports. Focusing on the methylation patterns of one paternally methylated gene (H19) and two maternally methylated genes (Peg3 and Snrpn), the team found that none showed impaired methylation until 35 days after STZ injection; however, embryo development and number of offspring were already affected on Day 15. On Day 35, methylation of Peg3 was significantly decreased, with an unmethylated oocyte rate nearly 22% higher in both types of diabetic mice compared to controls. H19 remained unaffected and effects on Snrpn were not significant. As for the female offspring of diabetic mothers, their oocytes did not appear to have any methylation abnormalities; however, due to the difficulty of producing offspring conceived after Day 15, it will be extremely difficult to determine whether those females are similarly unaffected.