Epigenomic heterogeneity and spatial organization during human reprogramming

Researchers integrated paired single-nucleus multiomics and spatial transcriptomics across human fibroblast reprogramming time courses from four individuals, finding that transcriptional and epigenomic changes are not synchronized along successful and failed trajectories. DNA methylation heterogeneity declines during successful reprogramming, while failed populations either retain fibroblast-like methylation or fail to fully establish the iPSC regulatory state after chromatin opening and demethylation. Spatial analysis shows the two populations organize differently before overt iPSC colonies form, with successful reprogramming hotspots visible by day 3.