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

• 成果类型: Article
• 署名作者: Liu, Min; Yue, Yanzhu; Chen, Xubin; Xian, Kexin; Dong, Chao; Shi, Ming; Xiong, Haiqing; Tian, Kang; Li, Yuzhe; Zhang, Qiangfeng Cliff; He, Aibin
• 署名单位: Peking University; Peking University; Peking University; Jilin University; Chinese Academy of Medical Sciences - Peking Union Medical College; Institute of Hematology & Blood Diseases Hospital - CAMS; Peking Union Medical College; Tsinghua University; Tsinghua University; Tsinghua University; Peking University; Peking University; Peking University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-0997
• DOI: 10.1038/s41586-025-08656-1
• 发表日期: 2025-04-17
• 关键词: chromatin-state discovery; stem-cells; architecture; h3k4me3; fate; segregation; landscapes; DYNAMICS; ELEMENTS; domains

摘要

Substantial epigenetic resetting during early embryo development from fertilization to blastocyst formation ensures zygotic genome activation and leads to progressive cellular heterogeneities1, 2-3. 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.