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

Lin Xie; Ning Ding; Siqi Sheng; Honghong Zhang; He Yin; Lina Gao; Hui Zhang; Shengchao Ma; Anning Yang; Guizhong Li; Yun Jiao; Qing Shi; Yideng Jiang; Huiping Zhang

doi:10.3724/abbs.2023012

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

Acta Biochim Biophys Sin (Shanghai). 2023 Feb 25;55(2):1-13. doi: 10.3724/abbs.2023012.

Authors

Lin Xie^{1

2

3}, Ning Ding^{1

2

3}, Siqi Sheng^{1

2

3}, Honghong Zhang^{1

2

3}, He Yin^{1

2

4}, Lina Gao^{1

2

4}, Hui Zhang^{1

2

3}, Shengchao Ma^{1

2

3}, Anning Yang^{1

2

3}, Guizhong Li^{1

2

3}, Yun Jiao^{1

2

5}, Qing Shi⁶, Yideng Jiang^{1

2

3}, Huiping Zhang^{7

2

8}

Affiliations

¹ NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan 750004, China.
² Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan 750004, China.
³ School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China.
⁴ Department of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, China.
⁵ Department of Infectious Diseases, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
⁶ Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
⁷ Department of Medical Genetics, Maternal and Child Health of Hunan Province, Changsha 410008, China.
⁸ General Hospital of Ningxia Medical University, Yinchuan 750004, China.

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.

Keywords: DNA methyltransferase 3a; HOXA11; apoptosis; nervous system polycomb 1; preeclampsia.

MeSH terms

Apoptosis
DNA Methylation
Female
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Polycomb-Group Proteins / metabolism
Pre-Eclampsia* / genetics
Pre-Eclampsia* / metabolism
Pregnancy
Promoter Regions, Genetic
Trophoblasts* / metabolism

Substances

Polycomb-Group Proteins
HOXA11 protein, human
Homeodomain Proteins

Grants and funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. U21A20343, 82171682, and 82270492), the Natural Science Foundation of Ningxia Hui Autonomous Region (No. 2020AAC02038), the Key Research and Development Projects in Ningxia Hui Autonomous Region (Nos. 2019BFG02004, 2021BEG02028, 2020BEG03005, 2020BFH02003, and 2022BEG02054), and the Basic Scientific Research Operating Expenses from the public welfare research institutes at the central level of the Chinese Academy of Medical Sciences (No. 2019PT330002).