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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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Hauptverfasser: Scherer, Michael (VerfasserIn) , Singh, Indranil (VerfasserIn) , Braun, Martina Maria (VerfasserIn) , Szu-Tu, Chelsea (VerfasserIn) , Sanchez Sanchez, Pedro (VerfasserIn) , Lindenhofer, Dominik (VerfasserIn) , Jakobsen, Niels Asger (VerfasserIn) , Körber, Verena (VerfasserIn) , Kardorff, Michael (VerfasserIn) , Nitsch, Lena (VerfasserIn) , Kautz, Pauline (VerfasserIn) , Rühle, Julia (VerfasserIn) , Bianchi, Agostina (VerfasserIn) , Cozzuto, Luca (VerfasserIn) , Frömel, Robert (VerfasserIn) , Beneyto Calabuig, Sergi (VerfasserIn) , Lareau, Caleb (VerfasserIn) , Satpathy, Ansuman T. (VerfasserIn) , Beekman, Renée (VerfasserIn) , Steinmetz, Lars M. (VerfasserIn) , Raffel, Simon (VerfasserIn) , Ludwig, Leif S. (VerfasserIn) , Vyas, Paresh (VerfasserIn) , RodriguezFraticelli, Alejo (VerfasserIn) , Velten, Lars (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 10 July 2025
In: Nature
Year: 2025, Jahrgang: 643, Heft: 8071, Pages: 478487
ISSN:14764687
DOI:10.1038/s41586-025-09041-8
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41586-025-09041-8
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41586-025-09041-8
Volltext
Verfasserangaben: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 & Lars Velten
Beschreibung
Zusammenfassung: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.
Beschreibung:Online veröffentlicht: 21. Mai 2025
Gesehen am 20.10.2025
Beschreibung:Online Resource
ISSN:14764687
DOI:10.1038/s41586-025-09041-8

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