Establishment of chromatin architecture interplays with embryo hypertranscription

• 成果类型: Article
• 署名作者: 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
• 署名单位: Tsinghua University; Tsinghua University; Beijing University of Agriculture; Tsinghua University; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; University of Chinese Academy of Sciences, CAS; Jiangsu Academy of Agricultural Sciences
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09400-5
• 发表日期: 2025-10-02
• 关键词: gene-expression; rna-seq; mammalian genomes; cohesin; ctcf; h3k4me3; mouse; ORGANIZATION; domains; sites

摘要

After fertilization, early embryos undergo dissolution of conventional chromatin organization, including topologically associating domains (TADs)1,2. Zygotic genome activation then commences amid unusually slow de novo establishment of three-dimensional chromatin architecture2. 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.