Zhang Juan, Ataei Lamisa, Mittal Kirti, Wu Liang, Caldwell Lauren, Huynh Linh, Sarajideen Shahil, Tse Kevin, Simon Marie-Michelle, Mazid Md Abdul, Cook David P, Trcka Daniel, Kwan Tony, Hoffman Michael M, Wrana Jeffrey L, Esteban Miguel A, Ramalho-Santos Miguel
Lunenfeld-Tanenbaum Research Institute and Department of Molecular Genetics, University of Toronto, Toronto, ON M5T 3H7, Canada.
Lunenfeld-Tanenbaum Research Institute and Department of Molecular Genetics, University of Toronto, Toronto, ON M5T 3H7, Canada.
Dev Cell. 2025 Jan 20;60(2):186-203.e13. doi: 10.1016/j.devcel.2024.09.024. Epub 2024 Oct 15.
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.
确保人类早期胚胎发育进程的机制在很大程度上仍不为人知。在此，我们表明长散在核元件1（LINE1）转座子家族可防止人幼稚胚胎干细胞（hESCs）逆转为8细胞样细胞（8CLCs）。LINE1 RNA有助于维持H3K27me3水平，尤其是在19号染色体（Chr19）上。Chr19富含关键的8细胞期调控因子、H3K27me3以及在LINE1基因敲低或PRC2抑制后去抑制的基因。此外，Chr19在hESCs中与核仁紧密相关，但在8CLCs中相关性较弱。直接抑制PRC2活性可诱导8细胞期程序，并导致Chr19从核仁重新定位。LINE1基因敲低或PRC2抑制会诱导核仁应激，而核仁结构的破坏足以去抑制8细胞期程序。这些结果表明，LINE1 RNA和PRC2维持H3K27me3介导的基因抑制和三维核组织，以防止hESCs发生发育逆转。
