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，对胎儿在子宫内的生长和生存至关重要。胎盘形成和功能的缺陷可能对母亲和孩子产生深远的终身影响。胎盘的胎儿成分主要由高度特化的细胞组成，称为“滋养层”，其中有多种不同形态和功能的亚型。然而，在发育过程中，如何调节染色质可及性以控制不同滋养层亚型的出现还不完全清楚。我们将利用人类滋养层干细胞培养和操作的最新突破，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复合物是一种大的多组分复合物，通过组蛋白尾部乙酰化赖氨酸残基的溴结构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复合物是重要的滋养层细胞介导的母胎交换的形成。然而，在人类滋养层细胞中的BAF复合体功能的详细分析是缺乏的。此外，BPTF，最大的亚基的BPTF复合物，是高度表达在人类滋养层细胞，但其功能是未知的。我们将利用转录组学和功能基因组学的方法，提供一个全基因组的分子研究如何在人类滋养层细胞分化过程中实现染色质重塑，重点是对BAF和BAF复合物。这将提供重要的见解，如何控制基因表达，导致正确形成滋养层亚型，包括浸润性血管内滋养层与先兆子痫。因此，这些知识将是发现基因表达如何被错误调节，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."