During embryonic development, naive pluripotent epiblast cells transit to a formative state. The formative epiblast cells form a polarized epithelium, exhibit distinct transcriptional and epigenetic profiles 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 embryonic stem cell models to show that ESRRB is both required and sufficient to activate formative genes. Genetic inactivation of Esrrb leads to illegitimate expression of mesendoderm and extra-embryonic markers, impaired formative expression and failure to self-organize in 3D. Functionally, this results in impaired ability to generate formative stem cells and primordial germ cells in the absence of Esrrb. Computational modelling and genomic analyses revealed that ESRRB occupies key formative genes in naive cells and throughout the formative state. In so doing, ESRRB kickstarts the formative transition, leading to timely and unbiased capacity for multi-lineage differentiation.

在胚胎发育过程中，幼稚多能外胚层细胞转变为形成状态。形成性外胚层细胞形成极化上皮，表现出独特的转录和表观遗传特征，并获得分化成所有体细胞和种系谱系的能力。然而，我们对如何通过分子控制向形成状态的转变了解有限。在这里，我们使用小鼠胚胎干细胞模型来证明 ESRRB 对于激活形成基因来说是必要且充分的。Esrrb基因失活会导致中内胚层和胚胎外标记物的非法表达、形成性表达受损以及 3D 自组织失败。从功能上讲，这会导致在缺乏干细胞和原始生殖细胞的情况下生成形成干细胞和原始生殖细胞的能力受损。电子书。计算模型和基因组分析表明，ESRRB 占据幼稚细胞和整个形成状态的关键形成基因。通过这样做，ESRRB 启动了形成性转变，从而产生及时且公正的多谱系分化能力。