Department of Genetics, Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal.
i3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal.
J Assist Reprod Genet. 2021 Apr;38(4):791-801. doi: 10.1007/s10815-020-02047-3. Epub 2021 Jan 3.
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.
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.
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.
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.
胎儿宫内生长受限（IUGR）是一种胎儿生长并发症，可能是由于胎盘内母体向胎儿的营养物质传递效率低下所致。胎盘发育和功能异常与印迹基因的异常表达有关，而印迹基因受印迹控制区（ICR）的表观遗传修饰调控。在这项研究中，我们分析了已知与胎儿生长有关的印迹基因和参与 DNA 甲基化的表观遗传调节剂的表达，以及印迹控制区 KvDMR1 的 DNA 甲基化和全基因组 DNA 羟甲基化水平，在 IUGR 病例中。
通过 RT-qPCR 分析了 21 例 IUGR 病例和 9 例非 IUGR（对照）病例的足月胎盘样本中印迹基因和表观遗传调节剂的表达水平。此外，还通过亚硫酸氢盐测序和联合亚硫酸氢盐限制性分析（COBRA）技术分析了 KvDMR1 甲基化。此外，还测量了全基因组 DNA 甲基化和羟甲基化水平。
我们观察到 IUGR 胎盘中 PHLDA2、CDKN1C 和 PEG10 印迹基因以及 DNMT1、DNMT3A、DNMT3B 和 TET3 表观遗传调节剂的表达增加。KvDMR1 甲基化水平在 IUGR 组和对照组之间无差异；同样，全基因组 DNA 甲基化和羟甲基化也无差异。
我们的研究表明，表观遗传机制的失调，即印迹基因和表观遗传调节剂表达的增加，可能与 IUGR 的病因有关。因此，这项研究为 IUGR 的分子机制增加了知识，这可能有助于为 IUGR 妊娠的管理提供新的预测工具和未来的治疗选择。
