TWIST2

TWIST2 is a basic helix-loop-helix transcription factor that functions as a regulator of partial epithelial-to-mesenchymal transition (pEMT) in human endometrial epithelial cells, where it is directly repressed by HOXA10; upon HOXA10 loss, TWIST2 derepression drives mesenchymal gene expression and epithelial cell displacement, while TWIST2 knockdown restores epithelial identity and impairs embryo implantation [bio_10.1101_2025.01.10.631632].

1. 2025 Medium

   It was unknown how epithelial plasticity is transcriptionally controlled during embryo implantation; CUT&RUN and transcriptomic profiling revealed that HOXA10 directly represses TWIST2, and that TWIST2 derepression is both necessary and sufficient to drive pEMT in endometrial epithelium, establishing a mutually antagonistic HOXA10–TWIST2 circuit governing implantation competence.

   Evidence CUT&RUN, transcriptomic profiling, siRNA knockdown in human endometrial epithelial cells, in vivo mouse/hamster/monkey models, cell motility assays (preprint)

   PMID:bio_10.1101_2025.01.10.631632

   Open questions at the time

   • Single preprint study; findings have not been independently replicated or peer-reviewed
   • Direct TWIST2 transcriptional targets in endometrial cells have not been identified
   • Whether TWIST2 functions similarly in EMT contexts outside the endometrium is not addressed

• The downstream transcriptional targets of TWIST2 in endometrial pEMT, its chromatin-level mechanism of action, and its broader relevance to other EMT-dependent processes remain uncharacterized.
• No genome-wide identification of direct TWIST2 target genes
• No structural or biochemical characterization of TWIST2 DNA-binding specificity in this context
• Relationship to other EMT-inducing transcription factors (e.g., SNAI1, ZEB1) not established