2. Academic Validation
  3. Krüppel-like factor 5 rewires NANOG regulatory network to activate human naive pluripotency specific LTR7Ys and promote naive pluripotency

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

  • Cell Rep. 2022 Aug 23;40(8):111240. doi: 10.1016/j.celrep.2022.111240.
Zhipeng Ai 1,  Xinyu Xiang 2,  Yangquan Xiang 1,  Iwona Szczerbinska 3,  Yuli Qian 4,  Xiao Xu 1,  Chenyang Ma 1,  Yaqi Su 2,  Bing Gao 2,  Hao Shen 1,  Muhammad Nadzim Bin Ramli 3,  Di Chen 2,  Yue Liu 5,  Jia-Jie Hao 5,  Huck Hui Ng 6,  Dan Zhang 7,  Yun-Shen Chan 8,  Wanlu Liu 9,  Hongqing Liang 10
Affiliations

Affiliations

  • 1 Division of Human Reproduction and Developmental Genetics, Women's Hospital, and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310006, China.
  • 2 Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, 718 East Haizhou Road, Haining 314400, China.
  • 3 Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
  • 4 Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
  • 5 Guangzhou Laboratory, No. 9 Xing Dao Huan Bei Road, Guangzhou International Bio Island, Guangzhou 510005, China.
  • 6 Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117597, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 639798, Singapore.
  • 7 Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China. Electronic address: [email protected].
  • 8 Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Guangzhou Laboratory, No. 9 Xing Dao Huan Bei Road, Guangzhou International Bio Island, Guangzhou 510005, China. Electronic address: [email protected].
  • 9 Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, 718 East Haizhou Road, Haining 314400, China; Department of Orthopedic Surgery of the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310029, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
  • 10 Division of Human Reproduction and Developmental Genetics, Women's Hospital, and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310006, China. Electronic address: [email protected].
PMID: 36001968 DOI: 10.1016/j.celrep.2022.111240
Abstract

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.

Keywords

CP: stem cell research; ERVs; KLFs; cell potency; naive and primed pluripotency; transcription control; trophectoderm.

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