Young LINE-1 transposon 5′ UTRs marked by elongation factor ELL3 function as enhancers to regulate naive pluripotency in embryonic stem cells
Young LINE-1 transposon 5′ UTRs marked by elongation factor ELL3 function as enhancers to regulate naive pluripotency in embryonic stem cells
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DOI：
10.1038/s41556-023-01211-y
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发表时间：
2023-08-17
影响因子：
21.3
通讯作者：
Lin，Chengqi
中科院分区：
文献类型：
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作者：
Meng，Siyan;Liu，Xiaoxu;Lin，Chengqi
LINE-1是反转录转座子的主要分支，具有自主反转录转座活性。尽管存在潜在的遗传毒性，但LINE-1在早期胚胎中高度活化。在这里，我们表明，年轻的LINE-1的一个子集，L1Md_Ts，标记的RNA聚合酶II延伸因子ELL 3，并在小鼠胚胎干细胞中作为增强子的功能。ELL 3缺失使DNA羟甲基化酶TET 1和共阻遏物SIN 3A从L1Md_Ts中移出，但增加了溴结构域蛋白BRD 4的富集，导致5 hmC的丧失、H3 K27 ac的获得和L1Md_T附近基因的上调。具体而言，ELL 3占据并抑制位于Akt 3内的基于L1 Md_T的增强子，其编码AKT途径的关键调节子。ELL 3是在幼稚致敏过渡期间通过抑制Akt 3而适当激活ERK和有效关闭幼稚多能性所必需的。我们的研究揭示了由ELL 3控制的一个年轻LINE-1亚群在转录调控和小鼠早期胚胎发育中的增强子功能。
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 withinAkt3, which encodes a key regulator of AKT pathway. ELL3 is required for proper ERK activation and efficient shutdown of naïve pluripotency through inhibitingAkt3during 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.