Deregulation of imprinted genes expression and epigenetic regulators in placental tissue from intrauterine growth restriction
Deregulation of imprinted genes expression and epigenetic regulators in placental tissue from intrauterine growth restriction
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DOI：
10.1007/s10815-020-02047-3
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发表时间：
2021-01-03
影响因子：
3.1
通讯作者：
Doria, Sofia
中科院分区：
文献类型：
--
作者：
Canicais, Carla;Vasconcelos, Sara;Doria, Sofia
目的宫内生长受限（IUGR）是一种胎儿生长并发症，可由母体通过胎盘向胎儿的营养转移无效引起。胎盘发育和功能异常与印迹基因的异常表达有关，而印迹基因的异常表达受印迹控制区（ICRs）表观遗传修饰的调控。在这项研究中，我们分析了已知参与胎儿生长的印迹基因的表达和参与DNA甲基化的表观遗传调控因子，以及IUGR病例中KvDMR1印迹控制区的DNA甲基化和DNA羟甲基化的整体水平。方法采用RT-qPCR方法分析21例IUGR和9例非IUGR（对照组）足月胎盘中印迹基因和表观遗传调控因子的表达水平。此外，KvDMR1甲基化通过亚硫酸酯测序和亚硫酸酯限制分析（COBRA）技术进行分析。此外，还测量了总体DNA甲基化和羟甲基化水平。结果我们观察到IUGR胎盘中PHLDA2、CDKN1C和PEG10印迹基因以及DNMT1、DNMT3A、DNMT3B和TET3表观遗传调控因子的表达增加。在IUGR组和对照组之间，KvDMR1的甲基化水平没有差异；同样，检测到总体DNA甲基化和氢甲基化没有差异。结论表观遗传机制的失调，即印迹基因和表观遗传调控因子的表达增加，可能与IUGR的病因有关。因此，本研究为IUGR的分子机制增加了知识，这可能有助于新的预测工具和未来治疗IUGR妊娠的选择。
Purpose Intrauterine growth restriction (IUGR) is a fetal growth complication that can be caused by ineffective nutrient transfer from the mother to the fetus via the placenta. Abnormal placental development and function have been correlated with abnormal expression of imprinted genes, which are regulated by epigenetic modifications at imprinting control regions (ICRs). In this study, we analyzed the expression of imprinted genes known to be involved in fetal growth and epigenetic regulators involved in DNA methylation, as well as DNA methylation at the KvDMR1 imprinting control region and global levels of DNA hydroxymethylation, in IUGR cases. Methods Expression levels of imprinted genes and epigenetic regulators were analyzed in term placental samples from 21 IUGR cases and 9 non-IUGR (control) samples, by RT-qPCR. Additionally, KvDMR1 methylation was analyzed by bisulfite sequencing and combined bisulfite restriction analysis (COBRA) techniques. Moreover, global DNA methylation and hydroxymethylation levels were also measured. Results We observed increased expression of PHLDA2, CDKN1C, and PEG10 imprinted genes and of DNMT1, DNMT3A, DNMT3B, and TET3 epigenetic regulators in IUGR placentas. No differences in methylation levels at the KvDMR1 were observed between the IUGR and control groups; similarly, no differences in global DNA methylation and hydromethylation were detected. Conclusion Our study shows that deregulation of epigenetic mechanisms, namely increased expression of imprinted genes and epigenetic regulators, might be associated with IUGR etiology. Therefore, this study adds knowledge to the molecular mechanisms underlying IUGR, which may contribute to novel prediction tools and future therapeutic options for the management of IUGR pregnancies.