SP6 controls human cytotrophoblast fate decisions and trophoblast stem cell establishment by targeting MSX2 regulatory elements.

The commitment and differentiation of human placental progenitor cytotrophoblast (CT) cells are crucial for a successful pregnancy, but the underlying mechanism remains poorly understood. Here, we identified the transcription factor (TF), specificity protein 6 (SP6), as a human species-specific trophoblast lineage TF expressed in human placental CT cells. Using pluripotent stem cells as a model, we demonstrated that SP6 controls CT generation and the establishment of trophoblast stem cells (TSCs) and identified msh homeobox 2 (MSX2) as the downstream effector in these events. Mechanistically, we showed that SP6 interacts with histone acetyltransferase P300 to alter the landscape of H3K27ac at targeted regulatory elements, thereby favoring transcriptional activation and facilitating CT cell fate decisions and TSC maintenance. Our results established SP6 as a regulator of the human trophoblast lineage and implied its role in placental development and the pathogenies of placental diseases. [Display omitted] • SP6 is a human species-specific trophoblast lineage transcription factor • SP6 interacts with trophoblast core transcription factors and epigenetic modifiers • SP6 determines cytotrophoblast generation and TSC establishment via MSX2 • SP6 interacts with P300 to alter the H3K27ac landscape at MSX2 loci Chen et al. demonstrated that SP6 is a trophoblast lineage TF specific to human species. It plays a role in controlling cytotrophoblast cell fate decisions and trophoblast stem cell maintenance by modifying the histone status at target sites, positioning this TF within the network of human placenta development. [ABSTRACT FROM AUTHOR]