Regulation of trophoblast differentiation by BAF complex chromatin remodelling factors

胎盘是维持健康妊娠所必需的关键器官。所有的器官都由许多不同的细胞类型组成。在胎盘中，胎儿提供了一系列不同的高度专业化的细胞，称为滋养层细胞，这些细胞由一种称为滋养层干细胞(TSCs)的专门细胞类型形成，我们可以在实验室培养和研究这种细胞。妊娠并发症，如先兆子痫及其更严重的HELLP综合征，影响大约5%的怀孕，具有潜在的长期健康影响，是母婴死亡的主要原因之一。滋养层细胞的发育和行为缺陷在很大程度上与这些妊娠并发症有关，因此了解滋养层细胞的形成对于开发更好的诊断、治疗和管理方法来解决此类疾病至关重要。细胞的特性和行为在很大程度上由细胞内活跃的基因控制。基因是否活跃，从而细胞的身份，取决于控制基因激活的分子机制是否能接触到DNA。DNA的可及性由被称为“染色质重塑因子”的特殊蛋白质控制，因此这些因子控制滋养层细胞的发育和行为。特别是，以前的研究表明，染色质重塑因子的BAF复合体对于不同类型滋养细胞的正确形成和存活妊娠是重要的。在这个项目中，我们将研究BAF复合体是如何控制TSCs产生的不同滋养细胞类型的平衡，以及它们如何与其他蛋白质网络相互作用来实现这一点。我们的研究将告诉我们，细胞命运是如何在胎盘中被控制的。它将揭示控制滋养层形成的蛋白质和DNA序列，因此这些蛋白质和DNA序列可能发生突变，导致妊娠并发症。因此，最终结果将是我们对胎盘如何发育的基本理解的关键进步。这一新知识未来可以被用来开发与胎盘功能问题相关的妊娠障碍的治疗干预策略。

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.