Chen Mengyang, Fu Ruijiang, Chen Yiqian, Li Li, Wang Shou-Wen
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
School of Life Sciences, Westlake University, Hangzhou, China.
Nat Methods. 2025 Mar;22(3):488-498. doi: 10.1038/s41592-024-02567-1. Epub 2025 Jan 16.
In vivo lineage tracing holds great potential to reveal fundamental principles of tissue development and homeostasis. However, current lineage tracing in humans relies on extremely rare somatic mutations, which has limited temporal resolution and lineage accuracy. Here, we developed a generic lineage-tracing tool based on frequent epimutations on DNA methylation, enabled by our computational method MethylTree. Using single-cell genome-wide DNA methylation datasets with known lineage and phenotypic labels, MethylTree reconstructed lineage histories at nearly 100% accuracy across different cell types, developmental stages, and species. We demonstrated the epimutation-based single-cell multi-omic lineage tracing in mouse and human blood, where MethylTree recapitulated the differentiation hierarchy in hematopoiesis. Applying MethylTree to human embryos, we revealed early fate commitment at the four-cell stage. In native mouse blood, we identified ~250 clones of hematopoietic stem cells. MethylTree opens the door for high-resolution, noninvasive and multi-omic lineage tracing in humans and beyond.
体内谱系追踪在揭示组织发育和体内平衡的基本原理方面具有巨大潜力。然而，目前人类的谱系追踪依赖于极其罕见的体细胞突变，这限制了时间分辨率和谱系准确性。在此，我们基于DNA甲基化的频繁表观突变开发了一种通用的谱系追踪工具，这是由我们的计算方法MethylTree实现的。利用具有已知谱系和表型标签的单细胞全基因组DNA甲基化数据集，MethylTree在不同细胞类型、发育阶段和物种中以近100%的准确率重建了谱系历史。我们在小鼠和人类血液中展示了基于表观突变的单细胞多组学谱系追踪，其中MethylTree概括了造血过程中的分化层次。将MethylTree应用于人类胚胎，我们揭示了四细胞阶段的早期命运决定。在天然小鼠血液中，我们鉴定出约250个造血干细胞克隆。MethylTree为人类及其他生物的高分辨率、非侵入性和多组学谱系追踪打开了大门。
