Cooperation between NSPc1 and DNA methylation represses HOXA11 expression and promotes apoptosis of trophoblast cells during preeclampsia

Abstract

Accumulating evidence has shown that the apoptosis of trophoblast cells plays an important role in the pathogenesis of preeclampsia, and an intricate interplay between DNA methylation and polycomb group (PcG) protein-mediated gene silencing has been highlighted recently. Here, we provide evidence that the expression of nervous system polycomb 1 (NSPc1), a BMI1 homologous polycomb protein, is significantly elevated in trophoblast cells during preeclampsia, which accelerates trophoblast cell apoptosis. Since NSPc1 acts predominantly as a transcriptional inactivator that specifically represses HOXA11 expression in trophoblast cells during preeclampsia, we further show that NSPc1 is required for DNMT3a recruitment and maintenance of the DNA methylation in the HOXA11 promoter in trophoblast cells during preeclampsia. In addition, we find that the interplay of DNMT3a and NSPc1 represses the expression of HOXA11 and promotes trophoblast cell apoptosis. Taken together, these results indicate that the cooperation between NSPc1 and DNMT3a reduces HOXA11 expression in preeclampsia pathophysiology, which provides novel therapeutic approaches for targeted inhibition of trophoblast cell apoptosis during preeclampsia pathogenesis.

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

“…It is reported that DNMT3A enhances apoptosis of trophoblast cells in PE placenta by the binding of DNMT3A to the promotor of HOXA11 to hypermethylate the specific CpG islands and therefore to repress the expression of HOXA11 . Inhibition of DNMT3A reverses the apoptosis of trophoblast cells 38 . Interestingly, there are several researches reporting that the downregulation of DNMT3A could suppress trophoblast cell migration and invasion in PE placenta 27,29 .…”

“…Recently, the role of epigenetic modifications in PE has been a focal point of research. Some studies have indicated a negative correlation between placental DNA methylation levels and gene expression in PE and suggested that the dysfunction DNMTs could severely impede placental development and contribute to the occurrence of PE 17,21,37,38,49–51 . In brief, DNMTs play a crucial role in cell proliferation, apoptosis, migration, and invasion of placental trophoblast, consequently influencing the structural integrity and overall function of the placenta.…”

“…Some studies have indicated a negative correlation between placental DNA methylation levels and gene expression in PE and suggested that the dysfunction DNMTs could severely impede placental development and contribute to the occurrence of PE. 17,21,37,38,[49][50][51] In brief, DNMTs play a crucial role in cell proliferation, apoptosis, migration, and invasion of placental trophoblast, consequently influencing the structural integrity and overall function of the placenta. Considering that the abnormal STB and the reduced placental expression the syncytialization markers, such as GCM1, Syncytin-1 and Syncytin-2, are the characteristic features of PE, 52,53 the DNA methylation level in these markers regulated by DNMTs would exert a pivotal influence on placental development and the onset of PE.…”

“…Inhibition of reverses the apoptosis of trophoblast cells. 38 Interestingly, there are several researches reporting that the downregulation of DNMT3A could suppress trophoblast cell migration and invasion in PE placenta. 27,29 Andrews et al report the impaired development of STB and labyrinth in DNMT3B knockout mouse.…”

Excessive ER-phagy mediated by FAM134B contributes to trophoblast cell mitochondrial dysfunction in preeclampsia

“…Preeclampsia (PE), a pregnancy-specific disease characterized by hypertension, proteinuria, and multiple organ dysfunction, affects up to 10% of pregnancies worldwide [1]. The primary cause of PE is placental malformation, which is resulted from vascular dysfunction and hypertrophic trophoblastic apoptosis [2][3][4][5][6][7][8][9][10]. Therefore, maintaining normal trophoblast function plays a vital role in preventing PE.…”