AbstractWe present TADsplimer, the first computational tool to systematically detect topologically associating domain (TAD) splits and mergers across the genome between Hi-C samples. TADsplimer recaptures splits and mergers of TADs with high accuracy in simulation analyses and defines hundreds of TAD splits and mergers between pairs of different cell types, such as endothelial cells and fibroblasts. Our work reveals a key role for TAD remodeling in epigenetic regulation of transcription and delivers the first tool for the community to perform dynamic analysis of TAD splits and mergers in numerous biological and disease models.