Clonal tracing with somatic epimutations reveals dynamics of blood ageing

Michael Scherer, Indranil Singh, Martina Maria Braun, Chelsea Szu-Tu, Pedro Sanchez Sanchez, Dominik Lindenhofer, Niels Asger Jakobsen, Verena Körber, Michael Kardorff, Lena Nitsch, Pauline Kautz, Julia Rühle, Agostina Bianchi, Luca Cozzuto, Robert Frömel, Sergi Beneyto-Calabuig, Caleb Lareau, Ansuman T. Satpathy, Renée Beekman, Lars M. Steinmetz, Simon Raffel, Leif S. Ludwig, Paresh Vyas, Alejo Rodriguez-Fraticelli () and Lars Velten ()
Additional contact information
Michael Scherer: Barcelona Institute of Science and Technology
Indranil Singh: The Barcelona Institute of Science and Technology (BIST)
Martina Maria Braun: Barcelona Institute of Science and Technology
Chelsea Szu-Tu: Barcelona Institute of Science and Technology
Pedro Sanchez Sanchez: The Barcelona Institute of Science and Technology (BIST)
Dominik Lindenhofer: European Molecular Biology Laboratory (EMBL)
Niels Asger Jakobsen: University of Oxford
Verena Körber: University of Oxford
Michael Kardorff: University Hospital Heidelberg
Lena Nitsch: Berlin Institute of Health at Charité–Universitätsmedizin Berlin
Pauline Kautz: Berlin Institute of Health at Charité–Universitätsmedizin Berlin
Julia Rühle: Barcelona Institute of Science and Technology
Agostina Bianchi: Barcelona Institute of Science and Technology
Luca Cozzuto: Barcelona Institute of Science and Technology
Robert Frömel: Barcelona Institute of Science and Technology
Sergi Beneyto-Calabuig: Barcelona Institute of Science and Technology
Caleb Lareau: Memorial Sloan Kettering Cancer Center
Ansuman T. Satpathy: Stanford University School of Medicine
Renée Beekman: Barcelona Institute of Science and Technology
Lars M. Steinmetz: European Molecular Biology Laboratory (EMBL)
Simon Raffel: University Hospital Heidelberg
Leif S. Ludwig: Berlin Institute of Health at Charité–Universitätsmedizin Berlin
Paresh Vyas: University of Oxford
Alejo Rodriguez-Fraticelli: The Barcelona Institute of Science and Technology (BIST)
Lars Velten: Barcelona Institute of Science and Technology

Nature, 2025, vol. 643, issue 8071, 478-487

Abstract: Abstract Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.

Date: 2025
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DOI: 10.1038/s41586-025-09041-8

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