Embryonic stem cells possess the remarkable ability to self-organize into blastocyst-like structures upon induction. These stem cell-based embryo models serve as invaluable platforms for studying embryogenesis and therapeutic developments. Nevertheless, the specific intrinsic regulators that govern this potential for blastoid formation remain unknown. Here we demonstrate an intrinsic program that plays a crucial role in both blastoids and blastocysts across multiple species. We first establish metrics for grading the resemblance of blastoids to mouse blastocysts, and identify the differential activation of gene regulons involved in lineage specification among various blastoid grades. Notably, abrogation of nuclear receptor subfamily 1, group H, member 2 (Nr1h2) drastically reduces blastoid formation. Nr1h2 activation alone is sufficient to rewire conventional ESC into a distinct pluripotency state, enabling them to form blastoids with enhanced implantation capacity in the uterus and contribute to both embryonic and extraembryonic lineages in vivo. Through integrative multi-omics analyses, we uncover the broad regulatory role of Nr1h2 in the transcriptome, chromatin accessibility and epigenome, targeting genes associated with embryonic lineage and the transposable element SINE-B1. The Nr1h2-centred intrinsic program governs and drives the development of both blastoids and early embryos.

胚胎干细胞具有在诱导后自组织成囊胚样结构的非凡能力。这些基于干细胞的胚胎模型是研究胚胎发生和治疗发育的宝贵平台。然而，控制胚样形成潜力的特定内在调节因子仍然未知。在这里，我们展示了一个内在程序，该程序在多个物种的胚状体和囊胚中起着至关重要的作用。我们首先建立了对胚芽体与小鼠囊胚的相似性进行分级的指标，并确定了各种胚样等级之间参与谱系规范的基因调节子的差异激活。值得注意的是，核受体亚家族 1、H 组、成员 2 （Nr1h2） 的消除大大减少了胚样形成。单独的 Nr1h2 激活就足以将常规 ESC 重新连接成独特的多能性状态，使它们能够在子宫中形成具有增强着床能力的胚芽，并有助于体内胚胎和胚外谱系。通过整合多组学分析，我们揭示了 Nr1h2 在转录组、染色质可及性和表观基因组中的广泛调节作用，靶向与胚胎谱系和转座因子 SINE-B1 相关的基因。以 Nr1h2 为中心的内在程序管理和驱动胚芽体和早期胚胎的发育。