The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Guangzhou Medical University, Chinese Academy of Sciences, Guangzhou 511436, China.
Nucleic Acids Res. 2021 Dec 2;49(21):12167-12177. doi: 10.1093/nar/gkab1069.
The 3D genome organization is crucial for gene regulation. Although recent studies have revealed a uniquely relaxed genome conformation in totipotent early blastomeres of both fertilized and cloned embryos, how weakened higher-order chromatin structure is functionally linked to totipotency acquisition remains elusive. Using low-input Hi-C, ATAC-seq and ChIP-seq, we systematically examined the dynamics of 3D genome and epigenome during pluripotent to totipotent-like state transition in mouse embryonic stem cells (ESCs). The spontaneously converted 2-cell-embryo-like cells (2CLCs) exhibited more relaxed chromatin architecture compared to ESCs, including global weakening of both enhancer-promoter interactions and TAD insulation. While the former correlated with inactivation of ESC enhancers and down-regulation of pluripotent genes, the latter might facilitate contacts between the putative new enhancers arising in 2CLCs and neighboring 2C genes. Importantly, disruption of chromatin organization by depleting CTCF or the cohesin complex promoted the ESC to 2CLC transition. Our results thus establish a critical role of 3D genome organization in totipotency acquisition.
三维基因组组织对于基因调控至关重要。尽管最近的研究揭示了受精和克隆胚胎的全能早期卵裂球中独特的松弛基因组构象，但减弱的高级染色质结构如何与全能性获得功能相关仍然难以捉摸。使用低输入 Hi-C、ATAC-seq 和 ChIP-seq，我们系统地研究了小鼠胚胎干细胞（ESCs）从多能性到全能性样状态转变过程中三维基因组和表观基因组的动态变化。自发转化的 2-细胞胚胎样细胞（2CLCs）表现出比 ESCs 更松弛的染色质结构，包括增强子-启动子相互作用和 TAD 隔离的全局减弱。虽然前者与 ESC 增强子失活和多能基因下调相关，但后者可能有助于在 2CLCs 中出现的假定新增强子与邻近的 2C 基因之间的接触。重要的是，通过耗尽 CTCF 或黏合蛋白复合物破坏染色质组织会促进 ESC 向 2CLC 转变。因此，我们的研究结果确立了三维基因组组织在全能性获得中的关键作用。
