Regulation of trophoblast differentiation by BAF complex chromatin remodelling factors

BAF 复合染色质重塑因子对滋养层分化的调节

• 批准号: MR/S021531/1
• 负责人: Andrew Nelson
• 金额: $ 58.95万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS021531%2F1
• 关键词: Regulation; trophoblast; differentiation; BAF; complex

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.

胎盘是维持健康妊娠所需的重要器官。所有器官都是由许多不同类型的细胞组成的。在胎盘中，胎儿提供了一系列不同的高度特化的细胞，称为“滋养层细胞”，它由一种称为滋养层干细胞（TSCs）的单一特化细胞类型形成，我们可以在实验室中培养和研究。妊娠并发症，如先兆子痫及其更严重的HELLP综合征影响约5%的妊娠，具有潜在的长期健康影响，是孕产妇和婴儿死亡的主要原因之一。滋养层细胞的发育和行为缺陷与这些妊娠并发症密切相关，因此了解滋养层细胞如何形成对于开发更好的诊断、治疗和管理方法来解决这些疾病至关重要。细胞的特性和行为很大程度上是由细胞内活跃的基因控制的。基因是否活跃，从而决定细胞的身份，取决于控制基因激活的分子机制是否能接近DNA。DNA的可及性是由被称为“染色质重塑因子”的特殊蛋白质控制的，因此这些因子控制着滋养细胞的发育和行为。特别是，先前的研究表明，染色质重塑因子的BAF复合物对于不同滋养细胞类型的正确形成，从而实现可存活的妊娠是重要的。在这个项目中，我们将研究BAF复合物如何控制由tsc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目标。我们的研究将告诉我们细胞的命运是如何在胎盘中被控制的。它将揭示控制滋养细胞形成的蛋白质和DNA序列，从而可能导致妊娠并发症的突变。因此，最终的结果将是我们对胎盘如何发育的基本理解的关键进展。这一新知识可以在未来开发与胎盘功能问题相关的妊娠障碍的治疗干预策略。

项目成果

Eomes function is conserved between zebrafish and mouse and controls left-right organiser progenitor gene expression via interlocking feedforward loops.

• DOI: 10.3389/fcell.2022.982477
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5