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

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"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."