A barrier to human embryogenesis involves dysregulated 3D genome reprogramming and ZGA collapse
6 affiliations
- 1Key Laboratory for the Genetics of Development & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
- 2Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
- 3State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 4International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 5Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 6Key Laboratory of Fertility Preservation and Maintenance of the Ministry of Education, Ningxia Medical University, Yinchuan, China
Abstract
Early embryonic arrest (EEA) is a critical impediment in assisted reproductive technology, leading to lack of viable embryos. Despite its prevalence, the molecular basis of EEA remains elusive, and the contribution of 3D genome reorganization to this arrest remains largely unexplored. Here, we present an integrated analysis of chromatin architecture and transcriptome dynamics in arrested human embryos during zygotic genome activation (ZGA) stage. Our results reveal extensive chromosomal compartment switching, significant alterations in topologically associating domains (TADs) features, and disrupted chromatin looping in arrested embryos. It suggests that 3D genome reorganization and ZGA failure occur in arrested embryos, marked by reduced abundance of ZGA-critical genes, precocious activation of late-stage developmental pathways, suppression of RNA processing and ribosome biogenesis, and compromised energy metabolism. Additionally, we hypothesize that several transcription factors, including KLF17 and several ZNF family members, serve as regulators in the observed structural or functional changes during developmental arrest. Collectively, our findings suggest that defective 3D genome reprogramming and transcriptomic dysregulation during ZGA are associated with human embryonic arrest at the eight-cell stage. This study advances our understanding of human preimplantation development and its development failures by providing a valuable resource and a conceptual framework for future investigations.
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BibTeX
@article{cao2026barrier,
title = {{A barrier to human embryogenesis involves dysregulated 3D genome reprogramming and ZGA collapse}},
author = {Yuedi Cao and Geng G. Tian and Changliang Hou and Shenao Wang and Qing Lu and Shanhe Yu and Meiling Zhang and Yun Sun and Ji Wu},
journal = {Communications Biology},
year = {2026},
month = jul,
doi = {10.1038/s42003-026-10614-0},
url = {https://doi.org/10.1038/s42003-026-10614-0},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - A barrier to human embryogenesis involves dysregulated 3D genome reprogramming and ZGA collapse
AU - Yuedi Cao
AU - Geng G. Tian
AU - Changliang Hou
AU - Shenao Wang
AU - Qing Lu
AU - Shanhe Yu
AU - Meiling Zhang
AU - Yun Sun
AU - Ji Wu
PY - 2026
DA - 2026/07/07
JO - Communications Biology
DO - 10.1038/s42003-026-10614-0
UR - https://doi.org/10.1038/s42003-026-10614-0
AB - Early embryonic arrest (EEA) is a critical impediment in assisted reproductive technology, leading to lack of viable embryos. Despite its prevalence, the molecular basis of EEA remains elusive, and the contribution of 3D genome reorganization to this arrest remains largely unexplored. Here, we present an integrated analysis of chromatin architecture and transcriptome dynamics in arrested human embryos during zygotic genome activation (ZGA) stage. Our results reveal extensive chromosomal compartment switching, significant alterations in topologically associating domains (TADs) features, and disrupted chromatin looping in arrested embryos. It suggests that 3D genome reorganization and ZGA failure occur in arrested embryos, marked by reduced abundance of ZGA-critical genes, precocious activation of late-stage developmental pathways, suppression of RNA processing and ribosome biogenesis, and compromised energy metabolism. Additionally, we hypothesize that several transcription factors, including KLF17 and several ZNF family members, serve as regulators in the observed structural or functional changes during developmental arrest. Collectively, our findings suggest that defective 3D genome reprogramming and transcriptomic dysregulation during ZGA are associated with human embryonic arrest at the eight-cell stage. This study advances our understanding of human preimplantation development and its development failures by providing a valuable resource and a conceptual framework for future investigations.
SN - 2399-3642
ER -