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

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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.