BAP1/ASXL complex modulation regulates epithelial-mesenchymal transition during trophoblast differentiation and invasion.
BAP1/ASXL complex modulation regulates epithelial-mesenchymal transition during trophoblast differentiation and invasion.
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DOI：
10.7554/elife.63254
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发表时间：
2021-06-25
期刊：
影响因子：
7.7
通讯作者：
Hemberger M
中科院分区：
文献类型：
--
作者：
Perez-Garcia V;Lea G;Lopez-Jimenez P;Okkenhaug H;Burton GJ;Moffett A;Turco MY;Hemberger M
胎盘的正常功能取决于滋养层细胞分化并侵入子宫内膜以建立明确的母胎界面的最早发育阶段。此前，我们发现普遍表达的肿瘤抑制因子 BRCA1 相关蛋白 1 (BAP1) 是控制早期小鼠胎盘的新型分子节点的中心因子。然而，关于 BAP1 如何调节滋养层生物学的功能性见解仍然缺失。通过在小鼠滋养层干细胞中使用 CRISPR/Cas9 敲除和过表达技术，我们证明 BAP1 蛋白的下调对于在滋养层分化过程中触发上皮间质转化 (EMT) 至关重要，并与侵袭性增强相关。此外，我们发现 BAP1 抑制 EMT 进展的功能依赖于 BAP1 与其他性梳状 (ASXL1/2) 蛋白的结合，形成多梳抑制性去泛素酶 (PR-DUB) 复合物。最后，人滋养层干细胞中的内源表达模式和 BAP1 过表达实验表明，BAP1 在调节滋养层分化和 EMT 进展中的分子功能在小鼠和人类中是保守的。我们的结果表明，BAP1 的生理调节决定了滋养层的侵袭特性，描绘了 BAP1 PR-DUB 复合物在调节早期胎盘形成中的新作用。
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.