A barrier to human embryogenesis involves dysregulated 3D genome reprogramming and ZGA collapse.

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.