Establishment of chromatin architecture interplays with embryo hypertranscription

Guang Yu, Kai Xu, Weikun Xia, Ke Zhang, Qianhua Xu, Lijia Li, Zili Lin, Ling Liu, Bofeng Liu, Zhenhai Du, Xia Chen, Qiang Fan, Fangnong Lai, Wenying Wang, Lijuan Wang, Feng Kong, Chao Wang, Haiqiang Dai, Huili Wang and Wei Xie ()
Additional contact information
Guang Yu: Tsinghua University
Kai Xu: Tsinghua University
Weikun Xia: Tsinghua University
Ke Zhang: Tsinghua University
Qianhua Xu: Tsinghua University
Lijia Li: Tsinghua University
Zili Lin: Beijing University of Agriculture
Ling Liu: Tsinghua University
Bofeng Liu: Tsinghua University
Zhenhai Du: Tsinghua University
Xia Chen: Tsinghua University
Qiang Fan: Tsinghua University
Fangnong Lai: Tsinghua University
Wenying Wang: Tsinghua University
Lijuan Wang: Tsinghua University
Feng Kong: Tsinghua University
Chao Wang: Chinese Academy of Sciences
Haiqiang Dai: Chinese Academy of Sciences
Huili Wang: Jiangsu Academy of Agricultural Sciences
Wei Xie: Tsinghua University

Nature, 2025, vol. 646, issue 8083, 208-217

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-09400-5

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