LAUSR

Significance The human placenta contains progenitors that give rise to highly specialized trophoblast cell types, and failures in their differentiation are associated with placental pathologies. Importantly, transcription factors controlling these cell fate decisions in humans are poorly understood. Here, we uncovered MSX2 as a human-specific regulator of trophoblast cell identity and implicate its role in placental development and disease. We found that MSX2 interacts and cobinds many target genes with components of the SWI/SNF chromatin remodeling complex, suggesting a mechanistic link. Given the critical function of SWI/SNF in gene expression, organogenesis, and disease, we provided characterization of its composition and possible role in the placental context. Multiple placental pathologies are associated with failures in trophoblast differentiation, yet the underlying transcriptional regulation is poorly understood. Here, we discovered msh homeobox 2 (MSX2) as a key transcriptional regulator of trophoblast identity using the human trophoblast stem cell model. Depletion of MSX2 resulted in activation of the syncytiotrophoblast transcriptional program, while forced expression of MSX2 blocked it. We demonstrated that a large proportion of the affected genes were directly bound and regulated by MSX2 and identified components of the SWItch/Sucrose nonfermentable (SWI/SNF) complex as strong MSX2 interactors and target gene cobinders. MSX2 cooperated specifically with the SWI/SNF canonical BAF (cBAF) subcomplex and cooccupied, together with H3K27ac, a number of differentiation genes. Increased H3K27ac and cBAF occupancy upon MSX2 depletion imply that MSX2 prevents premature syncytiotrophoblast differentiation. Our findings established MSX2 as a repressor of the syncytiotrophoblast lineage and demonstrated its pivotal role in cell fate decisions that govern human placental development and disease.