Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, School of Life Sciences, THU-PKU Center for Life Science, Tsinghua University, Beijing 100084, China.
Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China.
Mol Cell. 2020 Jul 16;79(2):234-250.e9. doi: 10.1016/j.molcel.2020.06.001. Epub 2020 Jun 23.
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.
体细胞核移植 (SCNT) 可将体细胞核重编程为全能性状态。然而，该过程中 3D 染色质结构的重新组织仍知之甚少。使用低输入 Hi-C，我们揭示了在 SCNT 过程中，转移的核首先进入有丝分裂样状态（过早的染色质凝聚）。与受精胚胎不同，SCNT 胚胎在 1 细胞阶段显示出更强的拓扑关联域 (TAD)。TAD 在 2 细胞阶段变弱，随后逐渐巩固。1 细胞 SCNT 胚胎中的 A/B 区室明显较弱，随后逐渐增强。到 8 细胞阶段，体细胞染色质结构在很大程度上重置为胚胎模式。出乎意料的是，我们发现黏连蛋白抑制多能性和分化细胞中的少数合子基因组激活 (ZGA) 基因（2 细胞特异性基因），并且在供体细胞中预先耗尽黏连蛋白可促进少数 ZGA 和 SCNT。这些数据揭示了 SCNT 过程中 3D 染色质结构的多步重编程，并支持黏连蛋白在 TAD 形成和少数 ZGA 抑制中的双重作用。
