Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Riia St. 23, 51010 Tartu, Estonia.
Department of Obstetrics and Gynaecology, University of Tartu, L. Puusepa St. 8, Tartu 51014, Estonia.
Sci Rep. 2016 Dec 8;6:38439. doi: 10.1038/srep38439.
Recurrent pregnancy loss (RPL) concerns ~3% of couples aiming at childbirth. In the current study, transcriptomes and miRNomes of 1 trimester placental chorionic villi were analysed for 2 RPL cases (≥6 miscarriages) and normal, but electively terminated pregnancies (ETP; n = 8). Sequencing was performed on Illumina HiSeq 2000 platform. Differential expression analyses detected 51 (27%) transcripts with increased and 138 (73%) with decreased expression in RPL compared to ETP (DESeq: FDR P < 0.1 and DESeq2: <0.05). RPL samples had substantially decreased transcript levels of histones, regulatory RNAs and genes involved in telomere, spliceosome, ribosomal, mitochondrial and intra-cellular signalling functions. Downregulated expression of HIST1H1B and HIST1H4A (Wilcoxon test, fc≤0.372, P≤9.37 × 10) was validated in an extended sample by quantitative PCR (RPL, n = 14; ETP, n = 24). Several upregulated genes are linked to placental function and pregnancy complications: ATF4, C3, PHLDA2, GPX4, ICAM1, SLC16A2. Analysis of the miRNA-Seq dataset identified no large disturbances in RPL samples. Notably, nearly 2/3 of differentially expressed genes have binding sites for E2F transcription factors, coordinating mammalian endocycle and placental development. For a conceptus destined to miscarriage, the E2F TF-family represents a potential key coordinator in reprogramming the placental genome towards gradually stopping the maintenance of basic nuclear and cellular functions.
复发性流产（RPL）困扰着约 3%的生育夫妇。在本研究中，我们分析了 2 例 RPL 病例（≥6 次流产）和正常但选择性终止妊娠（ETP；n=8）的 1 个孕期胎盘绒毛膜绒毛的转录组和 miRNA 组。测序在 Illumina HiSeq 2000 平台上进行。差异表达分析检测到 51 个（27%）转录本在 RPL 中表达增加，138 个（73%）转录本表达减少，与 ETP 相比（DESeq：FDR P<0.1 和 DESeq2：<0.05）。RPL 样本的组蛋白、调节 RNA 以及参与端粒、剪接体、核糖体、线粒体和细胞内信号功能的基因的转录本水平显著降低。HIST1H1B 和 HIST1H4A 的下调表达（Wilcoxon 检验，fc≤0.372，P≤9.37×10）在通过定量 PCR 进行的扩展样本中得到验证（RPL，n=14；ETP，n=24）。几个上调的基因与胎盘功能和妊娠并发症有关：ATF4、C3、PHLDA2、GPX4、ICAM1、SLC16A2。miRNA-Seq 数据集的分析没有发现 RPL 样本中的大干扰。值得注意的是，近 2/3 的差异表达基因有 E2F 转录因子的结合位点，协调哺乳动物内周期和胎盘发育。对于注定要流产的胚胎，E2F TF 家族代表了一种潜在的关键协调因子，可将胎盘基因组重新编程，逐渐停止基本核和细胞功能的维持。
