In mammalian reproduction, a significant proportion of embryos fail to implant despite a receptive uterus, suggesting that defects in epithelial remodeling at the embryo-uterine interface contribute to implantation failure. The molecular programs enabling such remodeling remain incompletely understood. Here, we identify a conserved transcriptional circuit involving HOXA10 and TWIST2 that regulates epithelial plasticity in the endometrium via partial epithelial-to-mesenchymal transition (pEMT). HOXA10, a transcription factor essential for uterine receptivity, is specifically downregulated in the luminal epithelium at implantation in mice, hamsters, and monkeys. Integrated CUT&RUN and transcriptomic profiling in human endometrial epithelial cells reveal that HOXA10 directly activates epithelial gene networks and represses mesenchymal programs. HOXA10 loss, both in vitro and in vivo, induces a pEMT state with increased cell motility. Mechanistically, HOXA10 represses TWIST2, a core EMT regulator; its derepression promotes mesenchymal gene expression and epithelial cell migration. TWIST2 knockdown restores epithelial identity and impairs implantation. These findings establish a mutually antagonistic HOXA10-TWIST2 circuit as a key regulator of pEMT and epithelial remodeling during implantation.
© 2025. The Author(s).