The role of NUDT21 in microRNA-binging sites of EZH2 gene increases the of risk preeclampsia

Objectives: Preeclampsia (PE) is a major cause of mortality and morbidity among pregnant mothers and their fetuses worldwide. Recent studies have shown that several microRNAs (miRNAs) play crucial role in pathogenesis of PE patients; however, the mechanisms responsible for differences in miRNA function in PE largely remain to be determined. Materials and Methods: We studied that NUDT21 expression was markedly increased, whereas EZH2 was decreased in placental samples from patients with PE. We identified NUDT21 as an interaction partner of enhancer of zeste homologue 2 (EZH2). NUDT21 co-localized with EZH2 in the human trophoblast cell line, HTR-8/SVneo and NUDT21 was shown to bind to EZH2 in RNA immunoprecipitation assays. NUDT21 has previously been reported to be involved in alternative polyadenylation; thus, the interaction between NUDT21 and EZH2 may play an important role in the crosstalk between alternative polyadenylation (APA) and miRNA-mediated gene silencing in PE. Results: In the human trophoblast cell line HTR-8/SVneo, loss-of-function assays indicated that knockdown of NUDT21 suppressed cell proliferation, migration and tube formation. Furthermore, functional studies showed that NUDT21 elongated the 3'-UTR of mRNAs thereby exposing more miRNA binding sites (including miR138 and miR363), which enhanced the efficiency of miRNA-mediated gene silencing and promoted EZH2 binding. Conclusions: This is the first report about the relationship of NUDT21 and EZH2. The data indicate that the aberrant expression of NUDT21 contributes to PE by targeting 3'-UTR of EZH2 mRNA. These findings may provide novel targets for future investigations into therapeutic strategies for PE.