VGLL1 contributes to both the transcriptome and epigenome of the developing trophoblast compartment.

Early in human development, the very first group of cells to form is called the trophectoderm. These cells are essential: they help the embryo implant into the uterus and later develop into the placenta, the organ that supports the growing fetus. Although studies in animals have identified important signals that guide this early process, there are key differences between species—so understanding how the human placenta begins to form requires human-specific models. In this study, researchers used human pluripotent stem cells—cells that can become any cell type—to recreate the earliest steps of placental development in the laboratory. By treating these cells with a molecule called BMP4, they triggered them to develop into trophoblast-like cells, allowing the team to closely study the molecular events that occur during this transition. A main focus of the research was VGLL1, a gene previously identified as unique to the human placenta. The team found that although VGLL1 is activated by well-known trophoblast regulators, it plays a much bigger role than previously understood. VGLL1 helps strengthen key placental identity genes, boosts important growth signals through the EGFR pathway, and enhances WNT signaling, which supports proper cell development. The study also uncovered how VGLL1 influences the cell’s epigenetic landscape—the chemical marks on DNA that control gene activity. VGLL1 directly activates KDM6B, an enzyme that removes repressive molecular tags and helps switch on genes needed for placental formation. Altogether, this work identifies VGLL1 as a central coordinator that brings together multiple signaling pathways to establish the earliest human placental cells. These insights enhance our understanding of early human development and may help improve models for studying infertility, pregnancy complications, and placental disorders.