Abstract
Background: The reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) involves extensive transcriptional and epigenetic remodeling, yet the dynamics of three-dimensional (3D) genome architecture during this process remain poorly characterized. Methods: We performed high-resolution Hi-C at multiple time points during the reprogramming of mouse embryonic fibroblasts (MEFs) to iPSCs, capturing changes in A/B compartmentalization, topologically associating domains (TADs), and chromatin loops. Computational analysis integrated RNA-seq, ChIP-seq for key histone modifications and CTCF, and published reference epigenomes. Results: Reprogramming induced a progressive switch of several megabase-scale compartments from B (inactive) to A (active), particularly at loci containing pluripotency genes. TAD boundaries were largely stable but exhibited weakening at regions gaining new long-range interactions. The frequency of CTCF-anchored loops increased, and we identified cell-of-origin-specific 3D structures that persisted in established iPSC lines, consistent with prior reports [13]. Conclusions: Our results demonstrate that 3D genome reorganization is an integral part of the reprogramming process, with both conserved and cell-type-specific features, and provide a resource for understanding the epigenetic barriers to pluripotency acquisition.