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High-resolution, noninvasive single-cell lineage tracing in mice and humans based on DNA methylation epimutations

Chen, Mengyang, Fu, Ruijiang, Chen, Yiqian, Li, Li, Wang, Shou-Wen·2025·Nature Methods
DOI 10.1038/s41592-024-02567-1
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Abstract

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.

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Metadata

Authors
Chen, M., Fu, R., Chen, Y., Li, L., & Wang, S.-W.
Venue
Nature Methods
Publisher
Springer Science and Business Media LLC
Published
2025-01-16
Volume
22
Issue
3
Pages
488-498
ISSN
  • 1548-7091
  • 1548-7105
DOI
10.1038/s41592-024-02567-1
Cited by
58
References
16
Language
en
Licence

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