The spatial zonation of the placental vasculature is specified by epigenetic mechanisms [WGBS]

The labyrinthian fetoplacental capillary network is of vital importance for proper nourishment of the developing embryo. An inadequate function of the maternal-fetal circulation has emerged as one of the primary causes of placental insufficiency. Here, we show that the spatial zonation of the placental labyrinth vasculature is controlled by flow-regulated epigenetic mechanisms. The spatial and temporal analysis of gene transcription revealed a gradual change in the expression of epigenetic enzymes with the de novo DNA methyltransferase 3a (DNMT3A) as primary enzyme introducing DNA methylation in cells of the vascular system. Loss of Dnmt3a resulted in DNA hypomethylation and disturbance of the spatial-zonated placental gene expression. The resulting global DNA hypomethylation impaired the angiogenic capacity of endothelial cells. Global as well as endothelium-predominant deletion of Dnmt3a resulted in impaired placental vascularization and fetal growth retardation. A meta-analysis of human placental endothelial cell gene expression identified an association between preeclampsia and reduction of DNMT3A. Collectively, our study identified DMNT3A as critical methylome-regulator of placental endothelial cell gene expression and function with clinical implications for the pathogenesis of placental dysfunction, as it occurs during preeclampsia or fetal growth retardation. WGBS was performed from FACS-sorted placenta EC from litter-matched Dnmt3aflox/flox xCdh5-Cre and Dnmt3aflox/flox embryos in triplicates.

迷宫状的胎盘胎儿毛细血管网络对发育中胚胎的正常营养供给至关重要。母胎循环功能不全已被证实是胎盘功能不全的主要诱因之一。本研究证实，胎盘迷宫血管的空间分区受血流调控的表观遗传机制所支配。对基因转录的时空分析显示，表观遗传酶的表达呈渐进式变化，其中从头DNA甲基转移酶3a（DNMT3A）是在血管系统细胞中介导DNA甲基化的核心酶类。Dnmt3a缺失会导致DNA低甲基化，并破坏胎盘基因的空间分区表达模式。由此产生的全基因组DNA低甲基化会损害内皮细胞的血管生成能力。全身及内皮细胞特异性缺失Dnmt3a均会导致胎盘血管形成受损及胎儿生长迟缓。对人类胎盘内皮细胞基因表达的荟萃分析显示，子痫前期与DNMT3A表达降低存在相关性。综上，本研究证实DNMT3A是调控胎盘内皮细胞基因表达与功能的关键甲基化组因子，其与子痫前期、胎儿生长迟缓等情况下出现的胎盘功能不全的发病机制具有临床关联。本研究对同窝Dnmt3aflox/flox × Cdh5-Cre与Dnmt3aflox/flox胚胎的荧光激活细胞分选（FACS）纯化胎盘内皮细胞（EC）进行了三次生物学重复的全基因组亚硫酸氢盐测序（WGBS）。