Metabolic determinants of early placental development: Acetyl-coA metabolism and histone acetylation during trophoblast differentiation

主要的妊娠障碍源于怀孕前三个月胎盘发育不良。先兆子痫是一种妊娠特有的并发症，影响6-8%的妇女，可导致早产、胎儿生长受限，并增加母婴死亡的风险。妊娠早期胎盘形成受损导致的胎盘功能低下与子痫前期的发展有关。胎盘的形成依赖于被称为滋养层细胞的细胞转化为特定类型的细胞。这一过程依赖于多组基因之间的协调变化。这些基因的激活需要进入DNA区域，DNA区域是由包装DNA的组蛋白决定的。组蛋白中的化学修饰会影响它们包装DNA的能力。具体地说，乙酰辅酶A分子的加入会导致DNA从组蛋白上松动，从而促进基因激活。乙酰辅酶A是从营养物质中产生的，用于能量生产和组蛋白修饰。我将研究在滋养层细胞中产生乙酰辅酶A的过程，以及这些过程如何通过修改组蛋白来影响细胞转化和胎盘形成。此外，我将调查这些过程是否在先兆子痫中受损，以及这些受损的原因。这项研究的发现对于了解胎盘营养处理如何影响胎盘形成非常重要，并将帮助我们了解这一过程是如何在妊娠障碍中被干扰的，从而导致母亲和婴儿的不良结局。

Major pregnancy disorders originate from poor placental development in the first-trimester of pregnancy. Preeclampsia is a pregnancy-specific complication affecting 6-8% of women and can lead to premature delivery, fetal growth restriction, and increased risk of mortality to mother and child. A poorly functioning placenta caused by impaired placental formation in early pregnancy is implicated in the development of preeclampsia.Placental formation depends on cells called trophoblasts transforming into specialised cell-types. This process is dependent on the coordinated changes in sets of genes. Activation of these genes requires access to DNA regions that is determined by histone proteins that package DNA. Chemical modifications in histones influence their ability to package DNA. Specifically, addition of the molecule acetyl-coA leads to DNA loosening from histones facilitating gene activation. Acetyl-coA is generated from nutrients and used for energy production and histone modifications. I will examine the processes by which acetyl-coA is generated in trophoblasts and how these processes affect cell transformation and placental formation via modification of histone proteins. Moreover, I will investigate if these processes are impaired in preeclampsia and the causes of the impairments. The findings from this study are important for understanding how placental nutrient handling influences placental formation and will help us understand how this process is perturbed in a pregnancy disorder leading to poor outcomes in the mother and the baby.