<i>TP53BP2</i> Promotes Placental Autophagy and Preeclampsia via G9a and <i>DNMT1</i> Cooperatively Modulating E2F1

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.