Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
North Texas March of Dimes Birth Defects Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Endocrinology. 2019 Sep 1;160(9):2189-2203. doi: 10.1210/en.2019-00144.
Defective placental implantation and vascularization with accompanying hypoxia contribute to preeclampsia (PE), a leading cause of maternal and neonatal morbidity and mortality. Genetic and epigenetic mechanisms underlying differentiation of proliferative cytotrophoblasts (CytTs) to multinucleated syncytiotrophoblast (SynT) are incompletely defined. The SynT performs key functions in nutrient and gas exchange, hormone production, and protection of the fetus from rejection by the maternal immune system. In this study, we used chromatin immunoprecipitation sequencing of midgestation human trophoblasts before CytT and after SynT differentiation in primary culture to analyze changes in binding of RNA polymerase II (Pol II) and of active and repressive histone marks during SynT differentiation. Our findings reveal that increased Pol II binding to promoters of a subset of genes during trophoblast differentiation was closely correlated with active histone marks. This gene set was enriched in those controlling immune response and immune modulation, including interferon-induced tetratricopeptide repeat and placenta-specific glycoprotein gene family members. By contrast, genes downregulated during SynT differentiation included proinflammatory transcription factors ERG1, cFOS, and cJUN, as well as members of the NR4A orphan nuclear receptor subfamily, NUR77, NURR1, and NOR1. Downregulation of proinflammatory transcription factors upon SynT differentiation was associated with decreased promoter enrichment of endogenous H3K27Ac and H3K9Ac and enhanced binding of H3K9me3 and histone deacetylase 1. However, promoter enrichment of H3K27me3 was low in both CytT and SynT and was not altered with changes in gene expression. These findings provide important insight into mechanisms underlying human trophoblast differentiation and may identify therapeutic targets for placental disorders, such as PE.
胎盘植入和血管生成缺陷伴有伴随的缺氧导致子痫前期（PE），这是孕产妇和新生儿发病率和死亡率的主要原因。增殖细胞滋养细胞（CytT）向多核合胞滋养细胞（SynT）分化的遗传和表观遗传机制尚未完全定义。SynT 在营养和气体交换、激素产生以及保护胎儿免受母体免疫系统排斥方面发挥着关键作用。在这项研究中，我们使用了中孕期人类滋养细胞在原代培养中向 CytT 分化前后的染色质免疫沉淀测序，以分析在 SynT 分化过程中 RNA 聚合酶 II（Pol II）和活性及抑制性组蛋白标记物结合的变化。我们的发现表明，滋养细胞分化过程中 Pol II 与一组基因启动子的结合增加与活性组蛋白标记物密切相关。该基因集富含控制免疫反应和免疫调节的基因，包括干扰素诱导的四肽重复和胎盘特异性糖蛋白基因家族成员。相比之下，在 SynT 分化过程中下调的基因包括促炎转录因子 ERG1、cFOS 和 cJUN，以及 NR4A 孤儿核受体亚家族成员 NUR77、NURR1 和 NOR1。SynT 分化时促炎转录因子的下调与内源性 H3K27Ac 和 H3K9Ac 启动子富集减少以及 H3K9me3 和组蛋白去乙酰化酶 1 结合增强相关。然而，CytT 和 SynT 中 H3K27me3 的启动子富集均较低，并且随着基因表达的变化而没有改变。这些发现为人类滋养细胞分化的机制提供了重要的见解，并可能为胎盘疾病（如 PE）确定治疗靶点。
