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

Abstract

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.

• Authors: Ludivine Doridot, Dorothée Houry, Harald Gaillard, Sonia T Chelbi, Sandrine Barbaux, Daniel Vaiman
• Journal: Epigenetics (Epigenetics) Vol. 9 Issue 1 Pg. 142-51 (Jan 2014) ISSN: 1559-2308 [Electronic] United States
• PMID: 24081307 (Publication Type: Journal Article)

Chemical References

• MIRN34 microRNA, human
• MicroRNAs
• SERPINA3 protein, human
• Serpins
• Tumor Suppressor Protein p53

Topics

• Cell Line, Tumor
• Choriocarcinoma (genetics, metabolism)
• DNA Methylation
• Epigenesis, Genetic
• Female
• Humans
• Hypoxia (metabolism)
• MicroRNAs (genetics, metabolism)
• Placenta Diseases (genetics, metabolism)
• Pre-Eclampsia (genetics, metabolism)
• Pregnancy
• Promoter Regions, Genetic
• Serpins (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Uterine Neoplasms (genetics, metabolism)