79 / 2026-04-05 21:39:16

A Barrier to Human Embryogenesis: Dysregulated 3D Genome Reprogramming and the Collapse of Zygotic Genome Activation

Human ZGA, embryo development

Human in vitro fertilized embryos frequently exhibit restricted developmental potential, but the contribution of three-dimensional (3D) genome reorganization to early embryonic arrest remains largely unexplored. Here, we employed low-input Hi-C to systematically profile chromatin architecture and transcriptome dynamics in human embryos undergoing developmental arrest at the zygotic genome activation (ZGA) stage. Our results reveal extensive chromosomal compartment switching, significant alterations in topologically associating domains (TAD) features, and disrupted chromatin looping in arrested embryos. These structural alterations coincided with extensive transcriptomic dysregulation, marked by mis-expression of ZGA-critical genes, precocious activation of late-stage developmental pathways, suppression of RNA processing and ribosome biogenesis, and compromised energy metabolism.  Also, some candidate transcription factors including KLF17 and ZNF family members may correlate with embryonic arrest at 8-cell stage. Collectively, our findings demonstrate that defective 3D genome reprogramming coupled with transcriptomic dysregulation during ZGA underlies human embryonic arrest at the eight-cell stage, providing novel perspectives, valuable resources, and conceptual frameworks for investigating human preimplantation development and its associated developmental failures.