Abstract
A minority of 8C-like cells (8CLCs) expressing zygotic genome activation genes are captured in naïve embryonic stem cells (ESCs). However, how human ESCs transition into 8CLCs remains unknown. Here, we show that NELFA is dispensable in human primed ESCs but critical for naïve pluripotency, and its overexpression promotes the primed-to-naïve conversion. Notably, NELFA robustly induces 8CLCs that express human ZGA-specific genes in naïve ESCs. NELFA-induced human 8CLCs can contribute to both embryonic and extraembryonic developmental potential in the interspecies human-mouse chimera assay. Importantly, we also discovered that TP53 can activate the human 8CLCs state, and NELFA might be an upstream regulator of TP53. Furthermore, TP53 and NELFA are both essential for the complete transition to the 8CLC state. We also demonstrate that sustained NELFA overexpression in primed ESCs directs neural lineage specification. Thus, NELFA establishes and maintains naïve pluripotency and drives the 8CLC state, providing insights into early human embryogenesis.
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Acknowledgements
We thank the Wu lab and Surani lab members, including Fangyuan Liu, Yidi Geng, Zhe Liu, Kai Xiong, and Yiran Chen for their insightful comments and critical reading of the manuscript. We thank Novogene Co.,Ltd. and Wuhan Yingzi Gene Technology Co.,Ltd. for RNA-seq, DNA methylation seq, ATAC-seq and CUT&Tag-seq data analysis support. We thank Pentao Liu (The University of Hong Kong) for the kind gift of Tet-on-TRE, PB-EF1α-transposase, and PB-EF1α-rTTA plasmids. We also thank the Inner Mongolia University and Gurdon Institute Imaging Facility for helping us with imaging. This study is supported by the National Natural Science Foundation of China (32460837 to B.W.), the Inner Mongolia Natural Science Foundation Project for Young Scholars (2025JQ020 to B.W.), the National Science and Technology Major Project of China (2023ZD0405001 to B.W.), the Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region (NJYT23091 to B.W.), and the Program of Higher-Level Talents of Inner Mongolia University (10000-21311201/058 to B.W.); the National Key Research and Development Program of China (2022YFD1302202 to S.B.); the Program of “JIE BANG GUA SHUAI” of Inner Mongolia (2022JBGS0021 to X.L).
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Su, X., Yang, F., Neupane, J. et al. NELFA supports naïve pluripotency and drives 8C-like state in human embryonic stem cells. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72714-z
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DOI: https://doi.org/10.1038/s41467-026-72714-z