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.