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KLF17 promotes human naive pluripotency through repressing MAPK3 and ZIC2

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Abstract

The pluripotent state of embryonic stem cells (ESCs) is regulated by a sophisticated network of transcription factors. High expression of KLF17 has recently been identified as a hallmark of naive state of human ESCs (hESCs). However, the functional role of KLF17 in naive state is not clear. Here, by employing various gain and loss-of-function approaches, we demonstrate that KLF17 is essential for the maintenance of naive state and promotes the primed to naive state transition in hESCs. Mechanistically, we identify MAPK3 and ZIC2 as two direct targets repressed by KLF17. Overexpression of MAPK3 or ZIC2 partially blocks KLF17 from promoting the naive pluripotency. Furthermore, we find that human and mouse homologs of KLF17 retain conserved functions in promoting naive pluripotency of both species. Finally, we show that Klf17 may be essential for early embryo development in mouse. These findings demonstrate the important and conserved function of KLF17 in promoting naive pluripotency and reveal two essential transcriptional targets of KLF17 that underlie its function.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2018YFA0107601 and 2021YFA0100200) and the National Natural Science Foundation of China (91940302, 32130017, 82070294 and 32025007). We would like to thank members of Wang laboratory for critical reading and discussion of the paper. We thank Dr. Haoyi Wang for the gift of human embryonic stem cells and help with 5iL culture conditions. We thank the Flow Cytometry Core at National Center for Protein Sciences at Peking University, particularly Hongxia Lv, Yinghua Guo and Huan Yang for technical help with flow cytometry analysis.

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  1. Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China

    Shao-Hua Wang, Jing Hao, Chao Zhang, Fei-Fei Duan, Ya-Tzu Chiu, Ming Shi, Huiqing Cao & Yangming Wang

  2. Department of Medicine, Columbia Center for Human Development, Columbia Stem Cell Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, 10032, USA

    Xin Huang & Jihong Yang

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  1. Shao-Hua Wang
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Correspondence to Huiqing Cao or Yangming Wang.

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Wang, SH., Hao, J., Zhang, C. et al. KLF17 promotes human naive pluripotency through repressing MAPK3 and ZIC2. Sci. China Life Sci. 65, 1985–1997 (2022). https://doi.org/10.1007/s11427-021-2076-x

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