[FG] Mosimann Beatrice

Research Project  | 2 Project Members

1. Summary Background: Epigenetic mechanisms have been shown to be important in the regulation of gene expression, especially during tissue differentiation. These include methylation of regulatory gene sequences, as well as gene modulation by microRNAs (miRNAs). Preeclampsia (PE) and intra-uterine growth restriction (IUGR), two severe pregnancy-related disorders, have been proposed to involve aberrant differentiation of placental trophoblast tissues. miRNA molecules and epigenetically modified sequences can be detected in plasma in the form of cell-free nucleic acids. Working Hypothesis: PE and IUGR involve alterations in epigenetic regulation leading to aberrant trophoblast differentiation. Aim: To examine for possible epigenetic mechanisms (miRNA and methylation) controlling syncytialization, tissue modification/invasion or response to hypoxia/hyperoxia, in order to determine whether these play a role in the underlying etiology of PE and IUGR. Experiment Design: Use will be made of well established trophoblast-like cell lines (BeWo and Jeg-3). HeLa will serve as a negative control. Possible miRNA mechanisms regulating BeWo syncytialization and response to O2 stress will be examined for by deep sequencing . Epigenetically silenced genes regulating these events will be pharmacologically unmasked by treatment with 5-aza-2 -deoxycytodine. Alterations in protein expression levels will be confirmed by quantitative iTraq mass spectrometry. The pathological significance of miRNA or unmasked target genes will be examined for in placental tissue or isolated trophoblasts from pregnancies affected by PE / IUGR in comparison to healthy controls. The potential of such miRNA molecules, epigenetically modified sequences, or related proteins to serve as biomarkers will be examined for using a dedicated plasma bio-bank. Expected value of the proposed project: This research will shed new light on potentially crucial regulatory mechanisms controlling placental development and their possible dysregulation in pregnancy-related pathologies (PE/IUGR). Key regulatory molecules detected during this process could serve as the basis for a new generation of screening markers to reliably detect at-risk pregnancies. Key Words: miRNA, epigenetics, methylation, trophoblast, preeclampsia, cell-free nucleic acids