Analysis of Genome Architecture during SCNT Reveals a Role of Cohesin in Impeding Minor ZGA

• Published in: Molecular cell 2020-07, Vol.79 (2), p.234-250.e9
• Main Authors: Zhang, Ke, Wu, Dan-Ya, Zheng, Hui, Wang, Yao, Sun, Qiao-Ran, Liu, Xin, Wang, Li-Yan, Xiong, Wen-Jing, Wang, Qiujun, Rhodes, James D.P., Xu, Kai, Li, Lijia, Lin, Zili, Yu, Guang, Xia, Weikun, Huang, Bo, Du, Zhenhai, Yao, Yao, Nasmyth, Kim A., Klose, Robert J., Miao, Yi-Liang, Xie, Wei
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle Proteins - physiology; Cell Line; Cell Nucleus; Chromatin - physiology; Chromatin Assembly and Disassembly; chromatin reprogramming; Chromosomal Proteins, Non-Histone - physiology; cohesin; Cohesins; Computational Biology - methods; Datasets as Topic; early embryo; Embryonic Development; Female; Hi-C; Male; Mice; Mice, Inbred C57BL; minor ZGA; Nuclear Transfer Techniques; SCNT; somatic cell nuclear transfer; TAD; three-dimensional chromatin structure; Zygote - physiology
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.06.001

Somatic cell nuclear transfer (SCNT) can reprogram a somatic nucleus to a totipotent state. However, the re-organization of 3D chromatin structure in this process remains poorly understood. 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 topologically associating domains (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 and become increasingly strengthened afterward. By the 8-cell stage, somatic chromatin architecture is largely reset to embryonic patterns. Unexpectedly, we found cohesin represses minor zygotic genome activation (ZGA) genes (2-cell-specific genes) in pluripotent and differentiated cells, and pre-depleting cohesin in donor cells facilitates minor ZGA and SCNT. 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. [Display omitted] •Hi-C analysis of 3D chromatin architecture during somatic cell nuclear transfer (SCNT)•TADs and compartments exhibit remarkable reprogramming during SCNT•Cohesin represses minor ZGA genes in mESCs and differentiated cells•Cohesin pre-depletion in donor cells facilitates minor ZGA and SCNT Somatic cell nuclear transfer (SCNT) can reprogram a somatic nucleus to a totipotent state. By applying sisHi-C, Zhang et al. revealed a multi-step reprogramming of 3D chromatin architecture during SCNT. Surprisingly, they also found that pre-depleting cohesin in donor cells facilitates minor zygotic genome activation (ZGA) and SCNT.