Remodelling bivalent chromatin is essential for mouse peri-implantation embryogenesis

Yanhe Li^#¹, Jincan He^#², Yingdong Liu^#¹, Yi Hui³, Shanyao Liu¹, Yalin Zhang¹, Yan Xiong⁴, Tingting Xu⁵, Ziwen Xu¹, Zhuoao Zhang¹, Yan Zhang¹, Guang Yang², Jia Zhao², Dandan Bai¹, Xinyi Lei¹, Xiaochen Kou¹, Yanhong Zhao¹, Jing Du⁶, Zheng Guo⁶, Jiqing Yin¹, Xiaoqing Zhang^{3

5}, Congling Xu⁵, Yawei Gao¹, Miaoxin Chen¹, Hong Wang¹, Cizhong Jiang⁷, Shaorong Gao⁸, Wenqiang Liu⁹

Affiliations

¹ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
² Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
³ Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
⁴ Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁵ Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
⁶ Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China.
⁷ Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. czjiang@tongji.edu.cn.
⁸ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China. gaoshaorong@tongji.edu.cn.
⁹ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China. liuwenqiang@tongji.edu.cn.

^# Contributed equally.

PMID: 41034520
DOI: 10.1038/s41556-025-01776-w

Remodelling bivalent chromatin is essential for mouse peri-implantation embryogenesis

Yanhe Li et al. Nat Cell Biol. 2025.

. 2025 Oct 1.

doi: 10.1038/s41556-025-01776-w. Online ahead of print.

Authors

Affiliations

¹ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
² Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
³ Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
⁴ Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁵ Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
⁶ Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China.
⁷ Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. czjiang@tongji.edu.cn.
⁸ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China. gaoshaorong@tongji.edu.cn.
⁹ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China. liuwenqiang@tongji.edu.cn.

^# Contributed equally.

PMID: 41034520
DOI: 10.1038/s41556-025-01776-w

Abstract

Bivalency regulates developmental genes during lineage commitment. However, mechanisms governing bivalent domain establishment, maintenance and resolution in early embryogenesis remain unclear. Here we comprehensively trace bivalent chromatin remodelling throughout mouse peri-implantation development, revealing bifurcated establishment modes that partition epiblast and primitive endoderm regulatory programmes. We identify transiently maintained bivalent domains (TB domains) enriched in the epiblast, where gradual resolution fine-tunes pluripotency progression. Through targeted screening in embryos, we uncover 22 TB domain regulators, including the essential factor ZBTB17. Genetic ablation or degradation of ZBTB17 causes peri-implantation arrest. Mechanistically, ZBTB17 collaborates with KDM6A/B to resolve bivalency by removing H3K27me3 and priming the activation of key pluripotency genes. Remarkably, TB domain dynamics are evolutionarily shared in human pluripotent transitions, with ZBTB17 involvement despite species differences. Our work establishes a framework for bivalent chromatin regulation in early mammalian development and elucidates how its resolution precisely controls lineage commitment.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

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Remodelling bivalent chromatin is essential for mouse peri-implantation embryogenesis

Affiliations

Remodelling bivalent chromatin is essential for mouse peri-implantation embryogenesis

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources