Investigation of chromatin remodelling proteins in human trophoblast stem cell (TSC) identity, differentiation and function

胎盘是一个复杂的器官，对于胎儿在子宫内的生长和存活是必不可少的。胎盘形成和功能缺陷可能会对母亲和孩子产生深远的终生后果。胎盘的胎儿成分主要由被称为滋养层细胞的高度特化的细胞组成，滋养层细胞有多种亚型，具有不同的形态和功能。然而，在发育过程中如何调节染色质的可及性来控制不同滋养细胞亚型的出现，还不完全清楚。我们将利用最近在培养和操作人类滋养层干细胞方面的突破，为如何控制基因表达以确保人类胎盘的正常发育提供新的见解。BAF复合体是一个大型的多组分复合体，通过组蛋白尾部的乙酰化赖氨酸残基的溴域结合与染色质相互作用。然后，它影响核小体定位，从而影响启动子和增强子的可及性、基因表达和细胞命运。最近的证据表明，BAF复合体在滋养层细胞的形成中起着重要作用，这些滋养层细胞介导了母婴交换。然而，对BAF在人滋养层细胞中的复杂功能缺乏详细的分析。此外，BPTF是NURF复合体中最大的亚单位，在人滋养层细胞中高度表达，但其功能尚不清楚。我们将利用转录组学和功能基因组学方法，对人类滋养层细胞分化过程中如何实现染色质重塑提供全基因组的分子研究，重点是NURF和BAF复合体。这将为基因表达如何控制导致滋养细胞亚型的正确形成提供重要的见解，包括与先兆子痫有关的侵袭性血管内滋养细胞。因此，这一知识将是发现基因表达如何被错误调控，导致胎盘缺陷和妊娠并发症的关键一步。

"The placenta is a complex organ essential for foetal growth and survival within the uterus. Defects in placenta formation and function can have profound and lifelong consequences to both mother and child. The foetal component of the placenta consists largely of highly specialized cells known as "trophoblasts", of which there are multiple subtypes of distinct morphology and function. How chromatin accessibility is regulated to control emergence of different trophoblast subtypes during development, however, is not completely understood. We will exploit recent breakthroughs in culture and manipulation of human trophoblast stem cells to provide novel insights into how gene expression is controlled to ensure normal development of the human placenta.The BAF complex is a large multicomponent complex that interacts with chromatin through bromodomain binding of acetylated lysine residues on histone tails. It then influences nucleosome positioning and thus promoter and enhancer accessibility, gene expression and cell fate. Recent evidence suggests the BAF complex is important for formation of trophoblasts mediating maternal-foetal exchange. However, a detailed analysis of BAF complex function in human trophoblasts is lacking. Additionally, BPTF, the largest subunit of the NURF complex, is highly expressed in human trophoblasts but its function is unknown. We will exploit transcriptomics and functional genomics approaches to provide a genome-wide molecular investigation of how chromatin remodelling is achieved during human trophoblast differentiation, with a focus on the NURF and BAF complexes. This will provide major insights into how gene expression is controlled leading to correct formation of trophoblast subtypes, including invasive endovascular trophoblasts implicated in preeclampsia. Therefore, this knowledge will be a critical step towards discovering how gene expression is mis-regulated, leading to placental defects and pregnancy complications."