Abstract
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 in mouse trophoblast stem cells, 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. Moreover, we show that the function of BAP1 in suppressing EMT progression is dependent on the binding of BAP1 to additional sex comb-like (ASXL1/2) proteins to form the polycomb repressive deubiquitinase (PR-DUB) complex. Finally, both endogenous expression patterns and BAP1 overexpression experiments in human trophoblast stem cells suggest that the molecular function of BAP1 in regulating trophoblast differentiation and EMT progression is conserved in mice and humans. Our results reveal that the physiological modulation of BAP1 determines the invasive properties of the trophoblast, delineating a new role of the BAP1 PR-DUB complex in regulating early placentation.
Highlights
The placenta is a complex organ essential for nutrient and oxygen exchange between the mother and the developing fetus
In E9.5 placentae, BRCA1associated protein 1 (BAP1) immunoreactivity was prominent in the developing labyrinth and spongiotrophoblast layer as well as in maternal decidual cells, but was markedly less pronounced in trophoblast giant cells (TGCs), again suggesting that BAP1 is downregulated as trophoblast cells differentiate into TGCs (Figure 1—figure supplement 1D). These results indicate that BAP1 is highly expressed in undifferentiated trophoblast of the extraembryonic ectoderm (ExE) in vivo and in mouse trophoblast stem cells (mTSCs) in vitro
We show that BAP1 is highly expressed in both mTSCs and human trophoblast stem cells (hTSCs), and that its Figure 6 continued the choriocarcinoma cell lines JAR, JEG-3, and BeWo
Summary
The placenta is a complex organ essential for nutrient and oxygen exchange between the mother and the developing fetus. Trophoblast invasion allows attachment of the placenta to the uterus and mediates transformation of maternal spiral arteries, thereby ensuring an unimpeded blood flow into the intervillous space This process is fundamentally important to secure an adequate supply of resources to the fetus. A similar bias towards the TGC differentiation pathway at the expense of the syncytiotrophoblast lineage was observed in Bap1-null mouse trophoblast stem cells (mTSCs), suggesting a critical role for BAP1 in regulating trophoblast biology (Perez-Garcia et al, 2018). Understanding the mechanisms by which BAP1 regulates trophoblast differentiation and invasion will be important to uncover new molecular pathways involved in placental development, and to shed light into the signalling pathways altered in tumours where BAP1 is mutated. These data reveal a pivotal role of BAP1/ASXL complexes in regulating EMT as a requisite for trophoblast invasion and in regulating the finely tuned balance of lineage-specific differentiation into the various trophoblast subtypes
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