Introduction
Pre-eclampsia (PE ), which occurs in 3% to 7% of all pregnancies, is one of the leading causes of maternal and fetal morbidity and mortality worldwide1(). PE can be classified into two main types on the basis of the timing of its onset during pregnancy: early-onset and late-onset PE. Early-onset PE is a serious condition of pregnancy characterized by high blood pressure and often a significant amount of protein in the urine2(). It typically occurs before 34 weeks of gestation and cannot always be prevented3(). Insufficient trophoblast invasion, impaired uterine spiral artery remodeling, placental dysfunction, and endothelial dysfunction have been reported in early-onset PE pregnancies4(). Autophagy is a fundamental biological process in which cells degrade and recycle their own components. During early pregnancy, autophagy contributes to embryogenesis and is involved in the normal development of embryos56(,). Moreover, autophagy has been shown to accelerate trophoblast aging under conditions of oxygen deprivation, leading to exacerbated trophoblast dysfunction and deficiency7(). Clinical evidence has revealed that the pathophysiology of PE is related to increased LC3B-mediated autophagy8(). In addition, our previous study reported that autophagy is increased both in placentas from PE pregnancies and in trophoblasts under hypoxia and that the inhibition of autophagy may serve as a promising approach for adjuvant chemotherapy for PE9(). However, the exact role of autophagy in PE trophoblasts is unclear, and the initial factors that trigger this process are still poorly understood.
The tumor suppressor p53-binding protein 2 (TP53BP2) is a gene that encodes a protein that plays a significant role in regulating apoptosis10(). Endogenous TP53BP2 is damage inducible and modulates physiologic damage response pathways involved in diverse cellular functions11(). Recent studies have indicated that TP53BP2 is overexpressed in various tumor types and is a critical factor in tumorigenesis and development1213(,). In addition, TP53BP2 has a crucial influence on the proliferation and metastasis of triple-negative breast cancer cells, and the functional mechanism may be p53 independent to a great extent14(). Recent studies have shown that TP53BP2 can regulate autophagy through its N-terminal domain, which shares high structural similarity with ATG12 and LC313 because of the presence of the ubiquitin-fold sharing motif15(). Liu et al . reported that the overexpression of TP53BP2 inhibited autophagy at low-dose gp120 (a soluble envelope glycoprotein, 50 ng/mL) but induced autophagy at high-dose gp120 (200 ng/mL) in SH-SY5Y neuroblastoma cells; in turn, TP53BP2 knockdown attenuated the autophagy induced by high-dose gp12016(). These results suggested that TP53BP2 could regulate autophagy in diseases in a gp120 concentration-dependent manner. In addition, studies have shown that TP53BP2 inhibits RAS-induced autophagic activity to dictate the cellular response to RAS17(). Notably, many studies have shown that impaired trophoblast invasion and incomplete spiral artery remodeling are among the main causes of PE 1819(,). This observation of aberrant expression and the dual function of TP53BP2 led us to hypothesize that this molecule may be involved in the pathogenesis of PE through the regulation of autophagy.
Abnormal DNA methylation during placentation is the most important epigenetic factor correlated with PE 20(). Moreover, changes in histone modifications, such as acetylation, can also result in PE. Gene expression is regulated by various factors, such as the presence of DNA methylation marks or binding sites for transcription factors21(). Among histone modifications, histone methylation is a complex epigenetic mechanism that can activate or repress the transcription of target genes by altering the chromosomal structure, depending on the location of the methylation site22(). Interestingly, DNA methylation regulates gene expression by suppressing gene transcription. Similarly, it modifies the chromatin structure and interacts with other epigenetic modifications, thereby enabling more diverse regulation of gene expression2324(,). In mammals, the patterns of DNA methylation in somatic cells are determined mainly by the activity of DNMT125(). The direct interaction between DNMT1 and G9a is proposed to coordinate DNA methylation and H3K9 methylation during DNA replication26(). The transcription activity of a specific gene is known to be regulated by epigenetic markers and the interplay between transcription factors and the cis elements of specific promoters in a time- and space-dependent manner, which is intricately linked to gene expression27(). In addition, as a member of the E2F family, E2F1 is involved in regulating cell cycle progression, cell differentiation and DNA repair2829(,). Some evidence suggests that specific binding of E2F1 and/or E2F2 to CpG islands protects against de novo DNA methylation through nucleosome depletion30(). Moreover, increased expression of E2F1 and increased CpG hydroxy methylation of the E2F1 binding motif conjointly induce ESRP1 expression in breast cancer31(). Reports suggest that searching for abnormal DNA methylation (hypo/hyper) could be a reasonable approach to discover new markers related to PE, aiming to predict and understand the development of PE 32().
In this study, we discovered that TP53BP2 regulates autophagy and plays a crucial role in the development of early-onset PE. Mechanistically, the cooperation of G9a and DNMT1 suppresses the binding of E2F1 to the TP53BP2 promoter, leading to decreased TP53BP2 expression and autophagy in PE trophoblasts, providing a possible new theoretical basis for targeted therapy for early-onset PE.