Topologically associating domains define the 3D genome architecture of mouse totipotent-like stem cells

Totipotency is the first cell fate emerged from fertilization, but remains poorly understood at the molecular level. Totipotent blastomeres are characterized by the presence of topologically associating domains (TADs) with significantly weakened structural integrity. In this study, we performed high-resolution 3D genome architecture profiling of two established mouse totipotent-like models, chemically induced totipotent stem cells and totipotent blastomere-like cells, and revealed that both largely retained TADs found in inner cell mass /embryonic stem cells. Yet, amid the apparent TAD conservation, TAD strength was indeed considerably weakened upon the acquisition of totipotency. Integrative analysis of epigenetic and Hi-C data revealed that pluripotency genes underwent coordinated epigenetic landscape remodeling and 3D contact reorganization, which collectively drove pluripotency silencing. Epigenetic remodeling was also observed at totipotency gene loci. This work represents the first systematic effort to benchmark totipotency models at the 3D genome level and provides a framework to establish totipotency through 3D genome folding.