The mechanisms that ensure developmental progression in the early human embryo remain largely unknown. Here, we show that the family of long interspersed nuclear element 1 (LINE1) transposons prevents the reversion of naive human embryonic stem cells (hESCs) to 8-cell-like cells (8CLCs). LINE1 RNA contributes to maintenance of H3K27me3 levels, particularly at chromosome 19 (Chr19). Chr19 is enriched for key 8C regulators, H3K27me3, and genes derepressed upon LINE1 knockdown or PRC2 inhibition. Moreover, Chr19 is strongly associated with the nucleolus in hESCs but less in 8CLCs. Direct inhibition of PRC2 activity induces the 8C program and leads to a relocalization of Chr19 away from the nucleolus. LINE1 KD or PRC2 inhibition induces nucleolar stress, and disruption of nucleolar architecture is sufficient to de-repress the 8C program. These results indicate that LINE1 RNA and PRC2 maintain H3K27me3-mediated gene repression and 3D nuclear organization to prevent developmental reversion of hESCs.

中文翻译：

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LINE1 和 PRC2 控制人 ESC 中核仁组织和 8C 状态的抑制


确保早期人类胚胎发育进展的机制在很大程度上仍然未知。在这里，我们表明长穿散核元件 1 （LINE1） 转座子家族阻止了幼稚人胚胎干细胞 （hESC） 向 8 细胞样细胞 （8CLC） 的逆转。LINE1 RNA 有助于维持 H3K27me3 水平，尤其是在 19 号染色体 （Chr19） 处。Chr19 富含关键的 8C 调节因子 H3K27me3 和在 LINE1 敲低或 PRC2 抑制后去抑制的基因。此外，Chr19 与 hESC 中的核仁密切相关，但在 8CLC 中相关性较低。PRC2 活性的直接抑制诱导 8C 程序，并导致 Chr19 重新定位远离核仁。LINE1 KD 或 PRC2 抑制诱导核仁应激，核仁结构的破坏足以解除 8C 程序的抑制。这些结果表明，LINE1 RNA 和 PRC2 维持 H3K27me3 介导的基因抑制和 3D 核组织，以防止 hESCs 的发育倒退。