HOXA10-TWIST2 Antagonism Drives Partial Epithelial-to-Mesenchymal transition for Embryo Implantation

In mammalian reproduction, a significant proportion of embryos fail to implant despite a receptive uterus, suggesting that defects in epithelial remodelling at the embryo-uterine interface contribute to implantation failure. The molecular programs enabling such remodelling 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 displacement. 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 remodelling during implantation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/631632v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1ea7b16org.highwire.dtl.DTLVardef@136f3c5org.highwire.dtl.DTLVardef@be47a8org.highwire.dtl.DTLVardef@5283b2_HPS_FORMAT_FIGEXP M_FIG C_FIG