During embryogenesis, differentiation of pluripotent cells into somatic cell types depends both on signaling cues and intrinsic gene expression programs. While the molecular underpinnings of pluripotency are well mapped, much less is known on how mouse embryonic stem cells (mESCs) differentiate. Using RNA-Seq profiling during specification to the three germ layers, we showed that mESCs switched on condition-specific gene expression programs from the onset of the differentiation procedure and that primed pluripotency did not constitute an obligatory intermediate state. After inferring the gene network controlling mESC differentiation, we tested the role of the highly connected nodes by deleting them in a triple knock-in Sox1-Brachyury-Eomes mESC line reporting on ectoderm, mesoderm, and endoderm fates. This led to the identification of regulators of mESC differentiation that acted at several levels: Sp1 as a global break on differentiation, Nr5a2 controlling ectoderm specification, and notably Fos:Jun and Zfp354c as opposite switches between ectoderm and mesendoderm fate.

中文翻译：

---

基因调节网络控制多能性出口处的中胚层和外胚层之间的平衡。

在胚胎发生过程中，多能细胞向体细胞类型的分化取决于信号提示和内在基因表达程序。尽管对多能性的分子基础进行了很好的定位，但关于小鼠胚胎干细胞（mESCs）分化的方式知之甚少。在规范化过程中对三个胚芽层使用RNA-Seq谱分析，我们显示mESC从分化过程开始就启动了条件特异性基因表达程序，并且引发的多能性并不构成强制性的中间状态。推断出控制mESC分化的基因网络后，我们通过在有关外胚层，中胚层和内胚层命运的三联敲入Sox1-Brachyury-Eomes mESC系中删除它们来测试高度连接的节点的作用。