Krüppel-like factor 5 rewires NANOG regulatory network to activate human naive pluripotency specific LTR7Ys and promote naive pluripotency

• Main Authors: Ai, Zhipeng, Xiang, Xinyu, Xiang, Yangquan, Szczerbinska, Iwona, Qian, Yuli, Xu, Xiao, Ma, Chenyang, Su, Yaqi, Gao, Bing, Shen, Hao, Muhammad Nadzim Bin Ramli, Chen, Di, Liu, Yue, Hao, Jia-Jie, Ng, Huck Hui, Zhang, Dan, Chan, Yun-Shen, Liu, Wanlu, Liang, Hongqing
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Biological sciences; Cell Potency; Naive and Primed Pluripotency
• Online Access: https://hdl.handle.net/10356/164884
• Institution: Nanyang Technological University

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 promote stage-specific transcription network and cell potency.