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

Z Ai, X Xiang, Y Xiang, I Szczerbinska, Y Qian, X Xu… - Cell Reports, 2022 - cell.com
Z Ai, X Xiang, Y Xiang, I Szczerbinska, Y Qian, X Xu, C Ma, Y Su, B Gao, H Shen
Cell Reports, 2022cell.com
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 …
Summary
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.
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