BPS2026 – Nuclear deformations and epigenomic remodeling during maturation of a human epiblast model

Post-implantation, the pluripotent epiblast undergoes significant transcriptional and epigenetic changes to prepare for lineage specification during gastrulation. In this study, we examine epiblast maturation in a hiPSC-based model using engineered hydrogels capable of recapitulating epiblast morphology observed in vivo. We find that during lumenogenesis, as cells become polarized, nuclei experience significant volumetric compaction and translocation toward the basal surface. These drastic deformations require more energy than can be accounted for by cytoskeletal forces alone and are instead likely caused by changes in osmotic pressure. We looked at epigenetic changes in our in vitro model and observed a significant increase in euchromatin-associated modifications, such as H3K4me3 and H3K27ac. RNA-seq data indicates a broad increase in transcription during maturation. The timing of these changes coincides with the maturation of the cells’ apical surface, and the corresponding transition from actin-driven lumenogenesis to pressure-driven lumen expansion, a process recently reported by our lab. Although hiPSCs in this 3D epiblast model remain pluripotent during maturation, they show a distinct developmental trajectory in the transcriptomic and chromatin accessibility landscapes. Maturation is accompanied by increased ion transport channel expression and reduced ribosome biosynthesis; ATAC-seq data show differential accessible peak enrichment in genes responsible for these processes. These findings enhance our understanding of the molecular mechanisms driving epiblast maturation and highlight the utility of hiPSC-based models in recapitulating early developmental processes.