Clonal tracing with somatic epimutations reveals dynamics of blood ageing

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 s...

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Detalles Bibliográficos
Autores: Scherer, Michael, Singh, Indranil, Braun, Martina Maria, Szu Tu, Chelsea, Sánchez Sánchez, Pedro, Lindenhofer, Dominik, Jakobsen, Niels Asger, Körber,Verena, Kardorff, Michael, Nitsch, Lena, Kautz, Pauline, Rühle, Julia, Bianch, Agostina, Cozzuto, Luca, Frömel, Robert, Beneyto Calabuig, Sergi, Lareau, Caleb, Satpathy, Ansuman T., Beekman, Renée, Steinmetz, Lars M., Raffel, Simon, Ludwig, Leif S., Vyas, Paresh, Rodríguez Fraticelli, Alejo E., Velten, Lars
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/223950
Acceso en línea:https://hdl.handle.net/2445/223950
Access Level:acceso abierto
Palabra clave:Hematopoesi
Transformació cel·lular
Hematopoiesis
Cell transformation
Descripción
Sumario: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.

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