Chromatin-level interrogation of gene regulatory mechanisms controlling trophoblast stem cell differentiation

胎盘是一个复杂的器官，由母体和胎儿组织组成，对胎儿在子宫内的生长和存活至关重要。胎盘形成和功能的缺陷会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称为“滋养细胞”的高度特化的细胞组成，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细胞亚型的出现尚不完全清楚。BAF复合物是一个大的多组分复合物，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。已知BAF复合物组分的突变会破坏滋养细胞分化，然而，具体的滋养细胞表型和染色质靶点尚未得到充分的研究和描述。此外，BPTF是NURF染色质重塑复合体中最大的亚基。缺乏BPTF的胚胎已被证明在胚胎第10天在子宫内死亡，BPTF被认为是小鼠早期发育过程中滋养细胞分化的必要条件。我们将利用转录组学、功能基因组学和蛋白质组学方法，对滋养细胞分化过程中染色质重塑是如何实现的进行全基因组分子研究，重点关注NURF和BAF复合物。这将为了解基因表达如何被控制导致滋养细胞亚型的正确形成提供重要见解，包括与子痫前期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, composed of both maternal and foetal tissue, that is 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. 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. Mutation of BAF complex components is known to disrupt trophoblast differentiation, however, specific trophoblast phenotypes and chromatin targets are yet to be adequately studied and described. Additionally, BPTF is the largest subunit of the NURF chromatin remodelling complex. BPTF-deficient embryos have been shown to die in utero by embryonic day 10, and BPTF is considered essential for trophoblast differentiation during early mouse development.We will exploit transcriptomics, functional genomics and proteomics approaches to provide genome-wide molecular investigation of how chromatin remodelling is achieved during 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.