The nucleolus is a compartmentalized organelle in eukaryotic cells known to form during embryogenesis, yet how its layered architecture is transformed from homogenous precursor bodies is unclear, and any impacts of this formation on embryonic cell fate determination remain unknown. Here, we demonstrate that lncRNA LoNA tethers granular-component-enriched NPM1 to dense-fibrillar-component-enriched FBL and drives the formation of compartmentalized nucleolus via facilitating liquid–liquid phase separation of those two nucleolar proteins. Phenotypically, LoNA-deficient embryos show developmental arrest at the two-cell (2C) stage. Mechanistically, we demonstrate that LoNA deficiency leads to nucleolar formation failure, resulting in mislocalization and acetylation of NPM1 in the nucleoplasm. Acetylated NPM1 recruits and guides PRC2 complex to 2C genes, where PRC2 complex trimethylates H3K27, leading to transcriptional repression of these genes. Collectively, our findings reveal that lncRNA is required for the establishment of nucleolar structure, and this process has an impact on two-cell embryonic development via 2C transcriptional activation.

核仁是真核细胞中已知在胚胎发生过程中形成的一种区室化细胞器，但其层状结构如何从同质前体转变而来尚不清楚，并且这种形成对胚胎细胞命运决定的任何影响仍然未知。在这里，我们证明lncRNA LoNA将富含颗粒成分的NPM1连接到富含致密纤维成分的FBL，并通过促进这两种核仁蛋白的液-液相分离来驱动区室化核仁的形成。从表型上看，LoNA 缺陷的胚胎在双细胞 (2C) 阶段表现出发育停滞。从机制上讲，我们证明 LoNA 缺陷会导致核仁形成失败，导致核质中 NPM1 的错误定位和乙酰化。乙酰化的 NPM1 招募并引导 PRC2 复合物与 2C 基因结合，其中 PRC2 复合物使 H3K27 三甲基化，从而导致这些基因的转录抑制。总的来说，我们的研究结果表明，lncRNA 是核仁结构建立所必需的，并且该过程通过 2C 转录激活对双细胞胚胎发育产生影响。