Activity of the SWI/SNF complex is indispensable for syncytiotrophoblast formation.

Developmental transitions are characterized by coordinated changes in lineage-specific gene expression programs and chromatin states. Yet how these shifts in cell fate occur during placental development remains largely unknown. Here, we have used human trophoblast stem cells (hTSCs), genetic depletion and small-molecule inhibition of the SWI/SNF remodelling complex activity to address its role during syncytiotrophoblast (ST) differentiation. We found that SWI/SNF inhibition has a massive impact on gene expression, chromatin accessibility and histone modifications, particularly H3K27ac, resulting in ST differentiation failure. We also observed cell cycle defects, indicating that SWI/SNF is required for hTSCs to exit the cell cycle, which is a prerequisite for ST commitment. In addition, based on motif analysis of SWI/SNF target regions, we genetically tested several early ST candidate transcription factors. While GCM1, CEBPB and TBX3 are vital for ST differentiation, only GCM1 is sufficient to induce ST fate. Together, our results demonstrate that SWI/SNF activity is essential for lineage specification during placental development.