Inflammation-induced TET3/mir-3942 axis impedes the proliferation and invasion ability of trophoblast cells through destabilization of SERPINE1 in preeclampsia

Introduction: Abnormal expression of TET3 has been established to be associated with aberrant function of trophoblasts and lead to the progression of Preeclampsia (PE). Yet, the underlying mechanism of PE mediated by TET3 has not been elucidated. Methods: Target factors downstream of TET3 were identified by RNA-seq. Functional assays were used to assess the effects of TET3/SERPINE1 on the proliferation and invasion capabilities of HTR-8 and JAR. ChIP-PCR and Targeted bisulfite sequencing were conducted to detect the demethylation in the SERPINE1 promoter after inhibition of TET3. Luciferase reporter assays were performed to elucidate the mechanism by which miR-3942 binds to TET3/SERPINE1 mRNA. TET3 knockout mice and uterine artery ligation mice to further verify the reliability of this conclusion. Results: First, we identified genes mediated by TET3 in HTR-8 by RNA-seq. Then, we focus on SERPINE1 as the special downstream gene. The resulting data showed that SERPINE1 could reduce the proliferation and invasion. RNA-seq and mechanism analysis indicated that inhibition of TET3 suppressed the activation of SERPINE1 by reducing the demethylation of related CpG sites in the SERPINE1 promoter, thereby transcriptionally inactivating SERPINE1 expression. Moreover, luciferase reporter assay indicates that TET3 and SERPINE1 were direct targets of miR-3942. At last inflammatory cytokines may stimulate trophoblasts to enhance TET3 expression, promoting demethylation of SERPINE1 promoter and inducing SERPINE1 expression. Discussion: This study uncovers a TET3-mediated regulatory mechanism which can be stimulate by inflammatory cytokines in PE progression and suggests that targeting the miR-3942-TET3-SERPINE1-axis may provide new predictive and therapeutic interventions for PE.