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

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. [Display omitted] •Human naive pluripotency enriched LTR7Ys are activated by KLF4 and KLF5•KLF4 and KLF5 have both overlapping and distinct gene and TE targets•KLF5 rewires NANOG binding affinity from LTR7s to LTR7Ys•KLF5-NANOG activates LTR7Ys to boost naive gene expression and expands cell potency Endogenous retrovirus (ERV) elements are highly activated during early human embryonic development, but their regulation and function during embryogenesis are largely unclear. Ai et al. find two closely related ERVs that can be specifically activated by the naive and primed pluripotency transcription machineries, respectively, and that contribute to the cell fate plasticity.