Kru euro ppel-like factor 5 rewires NANOG regulatory network to activate human naive pluripotency specific LTR7Ys and promote naive pluripotency
Kru euro ppel-like factor 5 rewires NANOG regulatory network to activate human naive pluripotency specific LTR7Ys and promote naive pluripotency
复制标题
Krüppel 样因子 5 重新连接 NANOG 调控网络以激活人类幼稚多能性特异性 LTR7Y 并促进幼稚多能性
DOI：
10.1016/j.celrep.2022.111240
复制
发表时间：
2022-08-23
期刊：
影响因子：
8.8
通讯作者：
Liang, Hongqing
中科院分区：
文献类型：
--
作者：
Ai, Zhipeng;Xiang, Xinyu;Liang, Hongqing
据报道，内源性逆转录病毒（ERV）参与哺乳动物胚胎的植入前发育。在早期人类胚胎发生中，不同的 ERV 亚家族以高度阶段特异性的方式被激活。 ERV 激活的特异性如何实现仍然很大程度上未知。在这里，我们展示了LTR7Ys（人类桑葚胚-囊胚特异性HERVH长末端重复序列）如何被初始多能性转录网络激活的机制。我们发现 KLF5 与 NANOG 相互作用并重新连接以结合和调节 LTR7Ys；相反，在不存在 KLF5 的情况下，引物特异性 LTR7 优先与 NANOG 结合。多能干细胞中 KLF5 和 NANOG 对 LTR7Y 的特异性激活有助于人类特异性的初始多能性调节。 KLF5-LTR7Y 轴还促进滋养外胚层基因的表达，并有助于扩大细胞向胚胎外谱系的潜力。我们的研究表明，HERV 被细胞状态特异性转录机制激活，并促进阶段特异性转录网络和细胞效力。
Endogenous retroviruses (ERVs) have been reported to participate in pre-implantation development of mammalian embryos. In early human embryogenesis, different ERV sub-families are activated in a highly stage-specific manner. How the specificity of ERV activation is achieved remains largely unknown. Here, we demonstrate the mechanism of how LTR7Ys, the human morula-blastocyst-specific HERVH long terminal repeats, are activated by the naive pluripotency transcription network. We find that KLF5 interacts with and rewires NANOG to bind and regulate LTR7Ys; in contrast, the primed-specific LTR7s are preferentially bound by NANOG in the absence of KLF5. The specific activation of LTR7Ys by KLF5 and NANOG in pluripotent stem cells contributes to human-specific naive pluripotency regulation. KLF5-LTR7Y axis also promotes the expression of trophectoderm genes and contributes to the expanded cell potential toward extra-embryonic lineage. Our study suggests that HERVs are activated by cell-state-specific transcription machinery and pro-mote stage-specific transcription network and cell potency.