Regulation of trophoblast differentiation by BAF complex chromatin remodelling factors

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The placenta is a critical organ required to maintain a healthy pregnancy. All organs are made up of many distinct cell types. In the placenta the foetus contributes a range of different highly specialized cells called "trophoblasts", which form from a single specialized cell type called Trophoblast Stem Cells (TSCs) that we can culture and study in the laboratory. Pregnancy complications such as preeclampsia, and its more severe form HELLP Syndrome affect approximately 5% of pregnancies, have potentially long-term health implications and are one of the leading causes of maternal and infant death. Defective development and behaviour of trophoblasts is heavily implicated in these pregnancy complications so understanding how trophoblasts form is critical to developing better diagnostic, treatment and management methodologies to tackle such disorders. The identity and behaviour of cells is largely controlled by the genes that are active within the cell. Whether genes are active, and thus the identity of cells, depends on whether DNA is accessible to the molecular machinery that controls gene activation. The accessibility of DNA is controlled by specialised proteins known as "chromatin remodelling factors", so these factors control trophoblast development and behaviour. In particular, previous studies suggest that the BAF complex of chromatin remodelling factors are important for the correct formation of different trophoblast types, and thus a viable pregnancy.In this project we will investigate how BAF complexes control the balance of different trophoblast types arising from TSCs, and how they interact with a network of other proteins to do so. Our research will tell us how cell fate decisions are controlled in the placenta. It will reveal proteins and DNA sequences that control trophoblast formation, and which may therefore be mutated leading to pregnancy complications. The ultimate result will therefore be key advances in our fundamental understanding of how the placenta develops. This new knowledge can be exploited in future to develop therapeutic intervention strategies in pregnancy disorders that are associated with problems of placental function.