Abstract：
The etiology of preeclampsia (PE), a complex and multifactorial condition, remains incompletely understood. DNA methylation, which is primarily regulated by three DNA methyltransferases (DNMTs), DNMT1, DNMT3A, and DNMT3B, plays a vital role in early embryonic development and trophectoderm differentiation. Yet, how DNMTs modulate trophoblast fusion and PE development remains unclear. In this study, we found that the DNMTs expression was downregulated during trophoblast cells fusion. Downregulation of DNMTs was observed during the reconstruction of the denuded syncytiotrophoblast (STB) layer of placental explants. Additionally, overexpression of DNMTs inhibited trophoblast fusion. Conversely, treatment with the DNA methylation inhibitor 5-aza-CdR decreased the expression of DNMTs and promoted trophoblast fusion. A combined analysis of DNA methylation data and gene transcriptome data obtained from the primary cytotrophoblasts (CTBs) fusion process identified 104 potential methylation-regulated differentially expressed genes (MeDEGs) with upregulated expression due to DNA demethylation, including CD59, TNFAIP3, SDC1, and CDK6. The transcription regulation region (TRR) of TNFAIP3 showed a hypomethylation with induction of 5-aza-CdR, which facilitated CREB recruitment and thereby participated in regulating trophoblast fusion. More importantly, clinical correlation analysis of PE showed that the abnormal increase in DNMTs may be involved in the development of PE. This study identified placental DNA methylation-regulated genes that may contribute to PE, offering a novel perspective on the role of epigenetics in trophoblast fusion and its implication in PE development.
摘要：
先兆子痫（PE）的病因，复杂的多因素条件，仍然不完全理解。DNA甲基化，主要由三种DNA甲基转移酶（DNMTs）调节，DNMT1,DNMT3A,和DNMT3B，在早期胚胎发育和滋养外胚层分化中起着至关重要的作用。然而，DNMT如何调节滋养细胞融合和PE发育尚不清楚.在这项研究中,我们发现,在滋养细胞融合过程中,DNMTs表达下调.在胎盘外植体的裸露合胞体滋养层（STB）层的重建过程中观察到DNMT的下调。此外,DNMT的过表达抑制滋养细胞融合。相反，用DNA甲基化抑制剂5-aza-CdR治疗可降低DNMT的表达并促进滋养细胞融合。对从原代细胞滋养细胞（CTB）融合过程中获得的DNA甲基化数据和基因转录组数据的组合分析确定了104个潜在的甲基化调节的差异表达基因（MeDEG），由于DNA去甲基化而导致表达上调，包括CD59、TNFAIP3、SDC1和CDK6。TNFAIP3的转录调节区（TRR）显示出低甲基化，并诱导5-氮杂-CdR，促进CREB募集，从而参与调节滋养细胞融合。更重要的是,PE的临床相关性分析显示,DNMTs异常升高可能参与了PE的发生发展。这项研究确定了胎盘DNA甲基化调节基因，可能有助于PE，为表观遗传学在滋养细胞融合中的作用及其在PE发育中的意义提供了新的视角。
