The primitive endoderm supports lineage plasticity to enable regulative development [CUT&Tag]

Mammalian blastocyst formation involves the sequential specification of trophectoderm and the differentiation of inner cell mass into either epiblast or primitive endoderm. During this time, the embryo maintains a window of plasticity and able to redirect its cellular fate when challenged experimentally. In this context, we found that the primitive endoderm alone was capable of regenerating a complete blastocyst and continue normal postimplantation development. We identify an in vitro population similar to the early primitive endoderm in vivo that exhibits plasticity, forms three dimensional embryoid structures and exhibits multilineage competence in chimera assays. Here, we find OCT4 as the main player in collaborating with endodermal transcription factors to maintain pluripotent enhancers in a state that is primed for activation mediated by JAK/STAT signalling. Our observations support the notion that transcription factor persistence underlies plasticity in regulative development and highlights the importance of primitive endoderm in perturbed development.