Esrrb guides naive pluripotent cells through the formative transcriptional programme

During embryonic development, naive pluripotent epiblast cells transit to a formative state. Theformative epiblast cells form a polarised epithelium, exhibit distinct transcriptional and epigeneticprofiles and acquire competence to differentiate into all somatic and germline lineages. However,we have limited understanding of how the transition to a formative state is molecularly controlled.Here we used murine ESC models to show that ESRRB is both required and sufficient to activateformative genes. Genetic inactivation of Esrrb leads to illegitimate expression of mesendodermand extraembryonic markers, impaired formative expression and failure to self-organise in 3D.Functionally, this results in impaired ability to generate Formative Stem cells and primordialgerm cells in the absence of Esrrb. Computational modelling and genomic analyses revealed thatESRRB occupies key formative genes in naive cells and throughout the formative state. In sodoing, ESRRB kickstarts the formative transition, leading to timely and unbiased capacity formulti-lineage differentiation.