Rif1 and Hmgn3 regulate the conversion of murine trophoblast stem cells.

The appearance of trophectoderm (TE) is a hallmark event in preimplantation development during murine embryogenesis. However, little is known about the mechanisms underlying TE specification. We find that the depletion of Rif1 breaks down the barrier to the transition from embryonic stem cells (ESCs) to trophoblast stem cells (TSCs). Rif1-null-induced TSCs show typical TE properties and the potential to differentiate into terminal trophoblast lineages. Global transcriptome analysis reveal that Rif1 deletion activates 2-cell embryo (2C)-related genes and induces a totipotent-like state. Chimeric assays further confirm that Rif1-null ESCs contribute to the functional placenta in addition to the fetus on embryonic day 12.5. Furthermore, we show overexpression of Hmgn3, one of the key upregulated gene in Rif1-null ESCs, facilitates the induction of TSCs. Therefore, we report two key genes regulating the conversion of TSCs and provide insights for investigating TE specification.