Yu Guang, Xu Kai, Xia Weikun, Zhang Ke, Xu Qianhua, Li Lijia, Lin Zili, Liu Ling, Liu Bofeng, Du Zhenhai, Chen Xia, Fan Qiang, Lai Fangnong, Wang Wenying, Wang Lijuan, Kong Feng, Wang Chao, Dai Haiqiang, Wang Huili, Xie Wei
Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, New Cornerstone Science Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
Nature. 2025 Aug 13. doi: 10.1038/s41586-025-09400-5.
After fertilization, early embryos undergo dissolution of conventional chromatin organization, including topologically associating domains (TADs). Zygotic genome activation then commences amid unusually slow de novo establishment of three-dimensional chromatin architecture. How chromatin organization is established and how it interplays with transcription in early mammalian embryos remain elusive. Here we show that CTCF occupies chromatin throughout mouse early development. By contrast, cohesin poorly binds chromatin in one-cell embryos, coinciding with TAD dissolution. Cohesin binding then progressively increases from two- to eight-cell embryos, accompanying TAD establishment. Unexpectedly, strong 'genic cohesin islands' (GCIs) emerge across gene bodies of active genes in this period. GCI genes enrich for cell identity and regulatory genes, display broad H3K4me3 at promoters, and exhibit strong binding of transcription factors and the cohesin loader NIPBL at nearby enhancers. We show that transcription is hyperactive in two- to eight-cell embryos and is required for GCI formation. Conversely, induced transcription can also create GCIs. Finally, GCIs can function as insulation boundaries and form contact domains with nearby CTCF sites, enhancing both the transcription levels and stability of GCI genes. These data reveal a hypertranscription state in early embryos that both shapes and is fostered by the three-dimensional genome organization, revealing an intimate interplay between chromatin structure and transcription.
受精后，早期胚胎会经历传统染色质组织的解体，包括拓扑相关结构域（TADs）。合子基因组激活随后在三维染色质结构异常缓慢的从头建立过程中开始。在早期哺乳动物胚胎中，染色质组织是如何建立的以及它如何与转录相互作用仍然不清楚。在这里，我们表明CTCF在小鼠早期发育过程中占据染色质。相比之下，黏连蛋白在单细胞胚胎中与染色质的结合较差，这与TAD的解体相一致。黏连蛋白的结合随后从二细胞胚胎到八细胞胚胎逐渐增加，伴随着TAD的建立。出乎意料的是，在此期间，活跃基因的基因体上出现了强大的“基因黏连蛋白岛”（GCI）。GCI基因富集细胞身份和调控基因，在启动子处显示广泛的H3K4me3，并在附近增强子处表现出转录因子和黏连蛋白装载因子NIPBL的强结合。我们表明转录在二细胞到八细胞胚胎中高度活跃，并且是GCI形成所必需的。相反，诱导转录也可以产生GCI。最后，GCI可以作为绝缘边界并与附近的CTCF位点形成接触结构域，增强GCI基因的转录水平和稳定性。这些数据揭示了早期胚胎中的一种超转录状态，这种状态既塑造了三维基因组组织，又受到三维基因组组织的促进，揭示了染色质结构与转录之间的密切相互作用。
