Genome-coverage single-cell histone modifications for embryo lineage tracing

Min Liu, Yanzhu Yue, Xubin Chen, Kexin Xian, Chao Dong, Ming Shi, Haiqing Xiong, Kang Tian, Yuzhe Li, Qiangfeng Cliff Zhang and Aibin He ()
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Min Liu: Peking University
Yanzhu Yue: The First Hospital of Jilin University
Xubin Chen: Peking University
Kexin Xian: Peking University
Chao Dong: Peking University
Ming Shi: Peking University
Haiqing Xiong: Chinese Academy of Medical Sciences and Peking Union Medical College
Kang Tian: Tsinghua University
Yuzhe Li: Tsinghua University
Qiangfeng Cliff Zhang: Tsinghua University
Aibin He: Peking University

Nature, 2025, vol. 640, issue 8059, 828-839

Abstract: Abstract Substantial epigenetic resetting during early embryo development from fertilization to blastocyst formation ensures zygotic genome activation and leads to progressive cellular heterogeneities1–3. Mapping single-cell epigenomic profiles of core histone modifications that cover each individual cell is a fundamental goal in developmental biology. Here we develop target chromatin indexing and tagmentation (TACIT), a method that enabled genome-coverage single-cell profiling of seven histone modifications across mouse early embryos. We integrated these single-cell histone modifications with single-cell RNA sequencing data to chart a single-cell resolution epigenetic landscape. Multimodal chromatin-state annotations showed that the onset of zygotic genome activation at the early two-cell stage already primes heterogeneities in totipotency. We used machine learning to identify totipotency gene regulatory networks, including stage-specific transposable elements and putative transcription factors. CRISPR activation of a combination of these identified transcription factors induced totipotency activation in mouse embryonic stem cells. Together with single-cell co-profiles of multiple histone modifications, we developed a model that predicts the earliest cell branching towards the inner cell mass and the trophectoderm in latent multimodal space and identifies regulatory elements and previously unknown lineage-specifying transcription factors. Our work provides insights into single-cell epigenetic reprogramming, multimodal regulation of cellular lineages and cell-fate priming during mouse pre-implantation development.

Date: 2025
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DOI: 10.1038/s41586-025-08656-1

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