Evaluating the role of DNA methyltransferases in trophoblast fusion and preeclampsia development: Insights from methylation-regulated genes

作者全名：Yang, You-Fu; Li, Zhuo-Hang; Liu, Tai-Hang; Li, Cong; Xie, You-Long; Ge, Lu-Xing; Tang, Jing; Li, Fang-Fang; Luo, Xin; Fu, Li-Juan; Ding, Yu-Bin

作者地址：[Yang, You-Fu; Li, Zhuo-Hang; Li, Cong; Xie, You-Long; Ge, Lu-Xing; Li, Fang-Fang; Ding, Yu-Bin] Women & Childrens Hosp Chongqing Med Univ, Dept Obstet & Gynecol, Chongqing 401147, Peoples R China; [Yang, You-Fu; Li, Zhuo-Hang; Li, Cong; Xie, You-Long; Ge, Lu-Xing; Li, Fang-Fang; Ding, Yu-Bin] Chongqing Med Univ, Sch Publ Hlth, Joint Int Res Lab Reprod & Dev, Minist Educ China, Chongqing, Peoples R China; [Liu, Tai-Hang; Tang, Jing] Chongqing Med Univ, Sch Basic Med Sci, Dept Bioinformat, Chongqing, Peoples R China; [Luo, Xin] Chongqing Med Univ, Affiliated Hosp 1, Dept Obstet & Gynecol, Chongqing, Peoples R China; [Fu, Li-Juan] Chongqing Med Univ, Sch Tradit Chinese Med, Chongqing Key Lab Tradit Chinese Med Prevent & Cur, Chongqing, Peoples R China; [Fu, Li-Juan] Changsha Med Univ, Dept Basic Med Sci, Changsha, Hunan, Peoples R China

通信作者：Ding, YB (通讯作者)，Women & Childrens Hosp Chongqing Med Univ, Dept Obstet & Gynecol, Chongqing 401147, Peoples R China.

来源：FASEB JOURNAL

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001247775000001

JCR分区：Q1

影响因子：4.4

年份：2024

卷号：38

期号：13

开始页：　

结束页：　

文献类型：Article

关键词：DNA methylation; fusion; preeclampsia; trophoblast

摘要：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. Overexpression of DNA methyltransferases inhibits trophoblast fusion by impairing the hypomethylation of the transcription regulation region of key factors that modulate syncytialization and the recruitment and binding of CREB to these factors. This is involved in the onset and development of PE.image

基金机构：National Natural Science Foundation of China

基金资助正文：We acknowledge the support received from various sources during the course of this research.