Chromatin priming by transcription factor ELF3 confers transcriptional competence for amniotic differentiation on primed human embryonic stem cells

The self-organizing emergence of the amniotic lineage in synthetic human embryo models suggests that embryonic pluripotent cells possess an intrinsic potential to initiate extraembryonic amniotic differentiation. However, it remains poorly understood how this intrinsic amniotic competence is established and how it is linked to pluripotency. In this study, we found that the transcription factor ELF3, whose expression is restricted under primed pluripotency, governs the availability of amniotic competence. ELF3 is induced upon perturbation of primed pluripotency in vitro and expressed in cell populations associated with extraembryonic competence in vivo. We show that ectopic expression of ELF3 in primed pluripotent stem cells activates an amniotic transcriptional program, while genetic ablation of ELF3 impairs induction of amnion-related genes in an extraembryonic differentiation model. Mechanistically, ELF3 binds cis-regulatory elements of extraembryonic and amnion-related genes and increases their accessibility, thereby facilitating histone modifications, transcriptional cofactor recruitment, and transcriptional remodeling toward amniotic differentiation, including autocrine BMP-dependent signaling. Using a BMP4 enhancer as a model, we show that the ELF3-mediated increase in chromatin accessibility is required for TEAD/TAZ recruitment and subsequent transcriptional induction. These findings indicate that ELF3-mediated chromatin priming enables the retrieval of latent amniotic competence embedded within primed pluripotency, offering a new perspective on the developmental regulation of lineage plasticity in early human embryogenesis.