Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing, China.
Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Nat Cell Biol. 2023 Sep;25(9):1319-1331. doi: 10.1038/s41556-023-01211-y. Epub 2023 Aug 17.
LINE-1s are the major clade of retrotransposons with autonomous retrotransposition activity. Despite the potential genotoxicity, LINE-1s are highly activated in early embryos. Here we show that a subset of young LINE-1s, L1Md_Ts, are marked by the RNA polymerase II elongation factor ELL3, and function as enhancers in mouse embryonic stem cells. ELL3 depletion dislodges the DNA hydroxymethylase TET1 and the co-repressor SIN3A from L1Md_Ts, but increases the enrichment of the Bromodomain protein BRD4, leading to loss of 5hmC, gain of H3K27ac, and upregulation of the L1Md_T nearby genes. Specifically, ELL3 occupies and represses the L1Md_T-based enhancer located within Akt3, which encodes a key regulator of AKT pathway. ELL3 is required for proper ERK activation and efficient shutdown of naïve pluripotency through inhibiting Akt3 during naïve-primed transition. Our study reveals that the enhancer function of a subset of young LINE-1s controlled by ELL3 in transcription regulation and mouse early embryo development.
LINE-1s 是具有自主逆转录转座活性的主要逆转录转座子群。尽管 LINE-1s 具有潜在的遗传毒性，但它们在早期胚胎中高度激活。在这里，我们表明一组年轻的 LINE-1s，L1Md_Ts，由 RNA 聚合酶 II 延伸因子 ELL3 标记，并在小鼠胚胎干细胞中作为增强子发挥作用。ELL3 耗竭会使 DNA 羟甲基化酶 TET1 和共抑制因子 SIN3A 从 L1Md_Ts 上脱离，但会增加溴结构域蛋白 BRD4 的富集，导致 5hmC 的丢失、H3K27ac 的增加以及 L1Md_T 附近基因的上调。具体来说，ELL3 占据并抑制位于 Akt3 内的基于 L1Md_T 的增强子，Akt3 编码 AKT 通路的关键调节剂。ELL3 通过在原始-启动过渡期间抑制 Akt3，对于 ERK 的正确激活和原始多能性的有效关闭是必需的。我们的研究揭示了一组由 ELL3 在转录调控和小鼠早期胚胎发育中控制的年轻 LINE-1s 的增强子功能。
