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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Authors: 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
Format: article
Status:Published version
Publication Date:2025
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/223950
Online Access:https://hdl.handle.net/2445/223950
Access Level:Open access
Keyword:Hematopoesi
Transformació cel·lular
Hematopoiesis
Cell transformation
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repository_id_str
spelling Clonal tracing with somatic epimutations reveals dynamics of blood ageingScherer, MichaelSingh, IndranilBraun, Martina MariaSzu Tu, ChelseaSánchez Sánchez, PedroLindenhofer, DominikJakobsen, Niels AsgerKörber,VerenaKardorff, MichaelNitsch, LenaKautz, PaulineRühle, JuliaBianch, AgostinaCozzuto, LucaFrömel, RobertBeneyto Calabuig, SergiLareau, CalebSatpathy, Ansuman T.Beekman, RenéeSteinmetz, Lars M.Raffel, SimonLudwig, Leif S.Vyas, PareshRodríguez Fraticelli, Alejo E.Velten, LarsHematopoesiTransformació cel·lularHematopoiesisCell transformationCurrent 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.Springer Nature2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/223950Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/s41586-025-09041-8Nature, 2025, vol. 643, p. 478-487https://doi.org/10.1038/s41586-025-09041-8cc-by-nc-nd (c) Scherer, Michael et al., 2025http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2239502026-05-27T06:46:51Z
dc.title.none.fl_str_mv Clonal tracing with somatic epimutations reveals dynamics of blood ageing
title Clonal tracing with somatic epimutations reveals dynamics of blood ageing
spellingShingle Clonal tracing with somatic epimutations reveals dynamics of blood ageing
Scherer, Michael
Hematopoesi
Transformació cel·lular
Hematopoiesis
Cell transformation
title_short Clonal tracing with somatic epimutations reveals dynamics of blood ageing
title_full Clonal tracing with somatic epimutations reveals dynamics of blood ageing
title_fullStr Clonal tracing with somatic epimutations reveals dynamics of blood ageing
title_full_unstemmed Clonal tracing with somatic epimutations reveals dynamics of blood ageing
title_sort Clonal tracing with somatic epimutations reveals dynamics of blood ageing
dc.creator.none.fl_str_mv 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
author Scherer, Michael
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Hematopoesi
Transformació cel·lular
Hematopoiesis
Cell transformation
topic Hematopoesi
Transformació cel·lular
Hematopoiesis
Cell transformation
description 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.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/223950
url https://hdl.handle.net/2445/223950
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41586-025-09041-8
Nature, 2025, vol. 643, p. 478-487
https://doi.org/10.1038/s41586-025-09041-8
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Scherer, Michael et al., 2025
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Scherer, Michael et al., 2025
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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