*3.3. Histone Modifications*

Few studies addressed the question of histone code modifications in PE. Chakraborty and coll. evidenced a HIF-KDM3A-MMP12 signaling cascade that promotes trophoblast invasion and trophoblast-directed uterine spiral artery remodeling in rat placenta and human placental cells. Hypoxia drives HIF activation and KDM3A expression, which in return will alter the histone methylation status of genes promoting development of the invasive trophoblast lineage and tissue remodeling, illustrated with trophoblast-derived MMP12 activation [318]. Hypoxia was also shown to a ffect the histone demethylase JMJD6 (Jumonji domain containing protein 6) and JMJD6 demethylase activity was shown to be drastically reduced in PE placenta as compared to Control Placenta [319]. Very recently, the expressions of HDACs were investigated in PE placentas and only HDAC9 was found downregulated both at the mRNA and protein levels in syncytiotrophoblast cells. Knock-down of HDAC9 in HTR-8/SVneo cells inhibits trophoblast cell migration and invasion. TIMP3, an inhibitory of MMP involved in invasion and tissue remodeling, is a direct target of HDAC9, identified by ChIP and is upregulated in the absence of HDAC9 [320].
