# TP53BP2 Promotes Placental Autophagy and Preeclampsia via G9a and DNMT1 Cooperatively Modulating E2F1

## TL;DR

This study shows how TP53BP2 increases placental autophagy in preeclampsia through DNA methylation and epigenetic regulation, suggesting it as a potential treatment target.

## Contribution

The study reveals a novel mechanism involving TP53BP2, G9a, and DNMT1 in modulating autophagy and preeclampsia progression.

## Key findings

- TP53BP2 upregulation is linked to preeclampsia and promotes autophagy by releasing Beclin-1 from the Bcl-2/Beclin-1 complex.
- DNMT1 and G9a cooperatively repress TP53BP2 expression through DNA methylation and H3K9me2 modifications.
- TP53BP2 expression correlates with blood pressure and BMI but inversely with gestational age and birth weight in preeclampsia.

## Abstract

Preeclampsia (PE) is a pregnancy‐related disorder characterized by impaired migration and invasion of trophoblast cells. Recent studies have highlighted the critical role of autophagy in the development of PE. However, the precise mechanisms underlying the upregulation of autophagy in PE remain unclear. This study demonstrated that the expression of the tumor suppressor p53‐binding protein 2 (TP53BP2) is significantly upregulated in patients with PE. Silencing of TP53BP2 not only decreases autophagy but also attenuates PE progression in rat model. Moreover, TP53BP2 expression was positively correlated with blood pressure and body mass index (BMI) but negatively correlated with gestational age at delivery and neonatal birth weight. Our findings suggest that TP53BP2 enhances autophagy by promoting the release of Beclin‐1 from the Bcl‐2/Beclin‐1 complex. Additionally, DNMT1 and G9a cooperatively downregulated TP53BP2 expression by reducing DNA methylation and H3K9me2 enrichment in the TP53BP2 promoter region. Importantly, the cooperation between DNMT1 and G9a suppressed E2F1 binding to the TP53BP2 promoter, leading to transcriptional repression of TP53BP2 in trophoblasts. In brief, our study indicates that TP53BP2 promotes autophagy in trophoblasts through DNA methylation and H3K9me2‐mediated transcriptional regulation. These findings suggest that targeting TP53BP2 may be a potential therapeutic strategy for PE.

G9a, and DNA Methyltransferase1 (DNMT1) cooperatively modulates E2F1 on the promoter of tumor suppressor p53‐binding protein 2 (TP53BP2) increased autophagy in preeclampsia. TP53BP2 promotes autophagy in trophoblasts through DNA methylation and H3K9me2‐mediated transcriptional regulation.