北京大学何爱彬课题组的一项最新研究揭示了胚胎谱系追踪的基因组覆盖单细胞组蛋白修饰。这一研究成果发表在2025年2月26日出版的国际学术期刊《自然》上。

在这里，该课题组研究人员开发了靶染色质索引和标记（TACIT），这是一种能够在多主题早期胚胎中对7个组蛋白修饰进行基因组覆盖单细胞谱分析的方法。研究组将这些单细胞组蛋白修饰与单细胞RNA测序数据结合起来，绘制了单细胞分辨率表观遗传图谱。多模态染色质状态注解表明，在早期两细胞阶段开始的合子基因组激活已经引发了全能性的异质性。该课题组研究人员利用机器学习来识别全能性基因调控网络，包括特定阶段的转座元件和推定的转录因子。这些鉴定的转录因子组合的CRISPR激活诱导了多主题胚胎干细胞的全能性激活。结合多种组蛋白修饰的单细胞共谱，小组开发了一个模型，该模型预测了潜伏多模态空间中最早的细胞向内细胞群和滋养外胚层分支，并识别了调控元件和以前未知的谱系指定转录因子。他们的工作为单细胞表观遗传重编程、细胞谱系的多模态调控和细胞命运启动提供了见解。

研究人员表示，在胚胎从受精到囊胚形成的早期发育过程中，大量的表观遗传重置确保了合子基因组的激活，并导致细胞异质性的进展。绘制覆盖每个细胞的核心组蛋白修饰的单细胞表观基因组图谱是发育生物学的基本目标。

附：英文原文

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

Author: Liu, Min, Yue, Yanzhu, Chen, Xubin, Xian, Kexin, Dong, Chao, Shi, Ming, Xiong, Haiqing, Tian, Kang, Li, Yuzhe, Zhang, Qiangfeng Cliff, He, Aibin

Issue&Volume: 2025-02-26

Abstract: 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.

DOI: 10.1038/s41586-025-08656-1

Source: https://www.nature.com/articles/s41586-025-08656-1