Analysis of genome architecture during SCNT reveals a role of cohesin in repressing minor ZGA

Somatic cell nuclear transfer (SCNT) can reprogram a somatic nucleus to a totipotent state. However, the re-organization of three-dimensional chromatin structure in this process remains poorly understood. Here, using low-input Hi-C we revealed that during SCNT, the transferred nucleus first enters a mitotic-like state (premature chromatin condensation). Unlike fertilized embryos, SCNT embryos show stronger TADs at the 1-cell stage. TADs become weaker at the 2-cell stage, followed by gradual consolidation. Compartments A/B are markedly weak in 1-cell SCNT embryos, before becoming strengthened at the 2-cell stage and onward. Somatic chromatin compartments, TAD boundaries, and transcriptomes, with a few exceptions, are largely reset to embryonic patterns by the 8-cell stage. Unexpectedly, pre-depleting cohesin in donor cells facilitates minor zygotic genome activation (ZGA) and SCNT development. These data reveal multi-step reprogramming of 3D chromatin architecture during SCNT and support dual roles of cohesin in TAD formation and minor ZGA repression.