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.

中文翻译：

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宫内生长受限导致胎盘组织中印记基因表达和表观遗传调节因子的失调

目的

宫内生长受限 (IUGR) 是一种胎儿生长并发症，可能是由于母体通过胎盘向胎儿的营养传递无效引起的。胎盘发育和功能异常与印记基因的异常表达有关，这些基因受印记控制区 (ICR) 的表观遗传修饰调节。在这项研究中，我们分析了已知参与胎儿生长的印记基因和参与 DNA 甲基化的表观遗传调节因子的表达，以及在 IUGR 病例中 KvDMR1 印记控制区域的 DNA 甲基化和 DNA 羟甲基化的全球水平。

方法

通过 RT-qPCR 分析了来自 21 个 IUGR 病例和 9 个非 IUGR（对照）样本的足月胎盘样本中印记基因和表观遗传调节因子的表达水平。此外，通过亚硫酸氢盐测序和组合的亚硫酸氢盐限制性分析 (COBRA) 技术分析 KvDMR1 甲基化。此外，还测量了整体 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印记基因以及DNMT1、DNMT3A、DNMT3B和TET3表观遗传调节因子的表达增加。在 IUGR 和对照组之间没有观察到 KvDMR1 甲基化水平的差异；同样，没有检测到全局 DNA 甲基化和氢甲基化的差异。

结论

我们的研究表明，表观遗传机制的失调，即印记基因和表观遗传调节因子的表达增加，可能与 IUGR 病因有关。因此，这项研究为 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 妊娠的治疗选择。