Chromatin priming by transcription factor ELF3 awakens latent competence for human amniotic differentiation

The self-organizing emergence of amniotic lineage in synthetic human embryo models suggests that embryonic pluripotent cells possess an intrinsic potential to initiate the amniotic differentiation program. However, the molecular basis by which this intrinsic potential can be activated in pluripotent cells, and especially how it remains accessible even in the primed state, is poorly understood. In this study, we identified ELF3 as an amniotic transcription factor that is constrained by primed pluripotency. ELF3 is derepressed upon perturbation of primed pluripotency in vitro, and its expression pattern in vivo correlates with extraembryonic competence. Strikingly, ectopic expression of ELF3 alone is sufficient to convert primed embryonic stem cells into the amniotic lineage. This lineage-specifying role is underscored by the observation that genetic ablation of ELF3 impairs efficient amniotic differentiation from embryonic stem cells. Mechanistically, ELF3 binds cis-regulatory elements of extraembryonic and amniotic genes and promotes their accessibility, facilitating histone modifications and transcriptional cofactor recruitment that activate amniotic differentiation programs, including autocrine BMP-dependent signaling. The causal link was delineated at a newly identified BMP4 enhancer, where ELF3-mediated chromatin remodeling is required for TEAD/TAZ recruitment and transcriptional induction. These findings position ELF3 as a chromatin priming factor that establishes the entry point of a transcriptional cascade for amniotic differentiation. This study highlights that the amniotic competence embedded in primed pluripotency is dormant yet retrievable through ELF3 derepression, offering mechanistic insight into the transcription factor-mediated chromatin regulation underlying lineage plasticity during early human development.