BAP1/ASXL complex modulation regulates Epithelial-Mesenchymal Transition during trophoblast differentiation and invasion

Normal function of the placenta depends on the earliest developmental stages when trophoblast cells differentiate and invade into the endometrium to establish the definitive maternal-fetal interface. Previously, we identified the ubiquitously expressed tumour suppressor BRCA1-associated protein 1 (BAP1) as a central factor of a novel molecular node controlling early mouse placentation. However, functional insights into how BAP1 regulates trophoblast biology are still missing. Using CRISPR/Cas9 knockout and overexpression technology, here we demonstrate that the downregulation of BAP1 protein is essential to trigger epithelial-mesenchymal transition (EMT) during trophoblast differentiation associated with a gain of invasiveness. This function, which is conserved in mouse and humans, is dependent on the binding of BAP1 binding to Additional sex comb-like (ASXL1/2/3) proteins to form the Polycomb repressive deubiquitinase (PR-DUB) complex. Our results reveal that the physiological modulation of BAP1 determines the invasive properties of trophoblast, delineating a new role of the BAP1 PR-DUB complex in regulating early placentation.