miR-34a expression, epigenetic regulation, and function in human placental diseases

• DOI: 10.4161/epi.26196
• Publication Date: 2013-09-30T15:12:33Z
• Authors: Ludivine Doridot; Dorothée Houry; Harald Gaillard; Sonia T Chelbi; Sandrine Barbaux; Daniel Vaiman
• Keywords: 0301 basic medicine; Placenta Diseases; DNA Methylation; Epigenesis, Genetic; 3. Good health; MicroRNAs; 03 medical and health sciences; Pre-Eclampsia; Pregnancy; Cell Line, Tumor; Uterine Neoplasms; Humans; Female; Choriocarcinoma; Tumor Suppressor Protein p53; Hypoxia; Promoter Regions, Genetic; Serpins

Preeclampsia (PE) is the major pregnancy-induced hypertensive disorder responsible for maternal and fetal morbidity and mortality that can be associated with intrauterine growth restriction (IUGR). PE and IUGR are thought to be due to a placental defect, occurring early during pregnancy. Several placental microRNAs (miRNAs) have been shown to be deregulated in the context of placental diseases and could thus play a role in the pathophysiology of PE. Here, we show that pri-miR-34a is overexpressed in preeclamptic placentas and that its placental expression is much higher during the first trimester of pregnancy than at term, suggesting a possible developmental role. We explored pri-miR-34a regulation and showed that P53, a known activator of miR-34a, is reduced in all pathological placentas and that hypoxia can induce pri-miR-34a expression in JEG-3 cells. We also studied the methylation status of the miR-34a promoter and revealed hypomethylation in all preeclamptic placentas (associated or not with IUGR), whereas hypoxia induced a hypermethylation in JEG-3 cells at 72 h. Despite the overexpression of pri-miR-34a in preeclampsia, there was a striking decrease of the mature miR-34a in this condition, suggesting preeclampsia-driven alteration of pri-miR-34a maturation. SERPINA3, a protease inhibitor involved in placental diseases, is elevated in IUGR and PE. We show here that miR-34a overexpression in JEG-3 downregulates SERPINA3. The low level of mature miR-34a could thus be an important mechanism contributing to SERPINA3 upregulation in placental diseases. Overall, our results support a role for miR-34a in the pathophysiology of preeclampsia, through deregulation of the pri-miRNA expression and its altered maturation.