miR-34a expression, epigenetic regulation, and function in human placental diseases.
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.
['Doridot|Ludivine|L|', 'Houry|Dorothée|D|', 'Gaillard|Harald|H|', 'Chelbi|Sonia T|ST|', 'Barbaux|Sandrine|S|', 'Vaiman|Daniel|D|']
D045744:Cell Line, Tumor D002822:Choriocarcinoma D019175:DNA Methylation D044127:Epigenesis, Genetic D005260:Female D006801:Humans D000860:Hypoxia D035683:MicroRNAs D010922:Placenta Diseases D011225:Pre-Eclampsia D011247:Pregnancy D011401:Promoter Regions, Genetic D015843:Serpins D016159:Tumor Suppressor Protein p53 D014594:Uterine Neoplasms
preeclampsia placenta SERPINA3 intra-uterine growth restriction mir34a