Gestational omics of preterm birth Towards finding novel molecular regulators of labour

Preterm birth is associated with immediate and long-term morbidity as well as growth and developmental delay. Preterm delivery can be either idiopathic (spontaneous) or iatrogenic.
Therapeutic interventions targeting molecular factors involved in labour are not substantially reducing the rate of idiopathic preterm delivery and novel targets are needed. The process from uterine quiescence to strong synchronized contractions that expel the neonate, is an intricate process that involves the growing fetus, the placenta, the membranes, and the uterus. This thesis maps molecular mechanisms related to idiopathic preterm birth with the ambition to ultimately identify the initial trigger for parturition. We use pregnant mice as a model to determine how uterine gene expression changes across gestation and pinpoint TBX2 as one of the top upstream regulators in mid-gestation. By overexpression of TBX2 in cultured human myometrial cells, we show that TBX2 regulates the release of chemokines and cytokines classically associated with the transition from quiescent myometrium to a state of synchronized contractions. We also identify common myometrial upstream regulators for preterm and term labour. Using genome-wide methylation profiling we identify differentially methylated positions (DMPs) in umbilical cord blood unique to preterm vs term delivery of which 161 DMPs are identical to two other independent studies.
With respect to iatrogenic preterm birth, we report 178 genes across different chromosomal locations implicated in relation to preeclampsia and HELLP syndrome. We also examine the scope of certain confined placental mosaicisms (CPM) associated with an increased risk of preeclampsia and preterm birth.