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

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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.