Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
The University of Edinburgh, MRC Centre for Reproductive Health, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
Cell. 2018 Jul 12;174(2):391-405.e19. doi: 10.1016/j.cell.2018.05.043. Epub 2018 Jun 21.
Transposable elements represent nearly half of mammalian genomes and are generally described as parasites, or "junk DNA." The LINE1 retrotransposon is the most abundant class and is thought to be deleterious for cells, yet it is paradoxically highly expressed during early development. Here, we report that LINE1 plays essential roles in mouse embryonic stem cells (ESCs) and pre-implantation embryos. In ESCs, LINE1 acts as a nuclear RNA scaffold that recruits Nucleolin and Kap1/Trim28 to repress Dux, the master activator of a transcriptional program specific to the 2-cell embryo. In parallel, LINE1 RNA mediates binding of Nucleolin and Kap1 to rDNA, promoting rRNA synthesis and ESC self-renewal. In embryos, LINE1 RNA is required for Dux silencing, synthesis of rRNA, and exit from the 2-cell stage. The results reveal an essential partnership between LINE1 RNA, Nucleolin, Kap1, and peri-nucleolar chromatin in the regulation of transcription, developmental potency, and ESC self-renewal.
转座元件代表了近一半的哺乳动物基因组，通常被描述为寄生虫，或“垃圾 DNA”。LINE1 反转录转座子是最丰富的一类，被认为对细胞是有害的，但它在早期发育中却被高度表达。在这里，我们报告 LINE1 在小鼠胚胎干细胞（ESCs）和植入前胚胎中发挥重要作用。在 ESCs 中，LINE1 作为核 RNA 支架，招募核仁素和 Kap1/Trim28 来抑制 Dux，Dux 是一个专门针对 2 细胞胚胎的转录程序的主激活因子。与此同时，LINE1 RNA 介导核仁素和 Kap1 与 rDNA 的结合，促进 rRNA 的合成和 ESC 的自我更新。在胚胎中，LINE1 RNA 对于 Dux 的沉默、rRNA 的合成和 2 细胞阶段的退出都是必需的。这些结果揭示了 LINE1 RNA、核仁素、Kap1 和核周染色质在转录调控、发育潜能和 ESC 自我更新中的重要伙伴关系。
