Clonal tracing with somatic epimutations reveals dynamics of blood ageing

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  • dc.contributor.author Scherer, Michael
  • dc.contributor.author Braun, Martina Maria
  • dc.contributor.author Szu-Tu, Chelsea
  • dc.contributor.author Rühle, Julia
  • dc.contributor.author Bianchi, Agostina
  • dc.contributor.author Cozzuto, Luca
  • dc.contributor.author Frömel, Robert
  • dc.contributor.author Beneyto Calabuig, Sergi
  • dc.contributor.author Beekman, Renée
  • dc.contributor.author Velten, Lars
  • dc.date.accessioned 2025-09-05T06:25:39Z
  • dc.date.available 2025-09-05T06:25:39Z
  • dc.date.issued 2025
  • dc.description.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.
  • dc.description.sponsorship We thank staff at Mission Bio for support and at the CRG Core Technologies Programme, specifically to the CRG Genomics Unit for assistance with sequencing and the CRG/UPF Flow Cytometry Unit for flow sorting. Funding for this project was provided to L.V. by an EHA Research Grant award granted by the European Hematology Association, by the Fundación Asociación Española Contra el Cáncer (AECC laboratory grant) and by the the Ministry of Science and Innovation (PID2023-146699NB-I00 funded by MCIN / AEI / 10.13039/501100011033 / FEDER, UE). M.S. was supported through the Walter Benjamin Fellowship funded by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, reference 493935791) and a postdoctoral fellowship provided by the Dr. Rurainski Foundation for Cancer Research. I.S. was supported through the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no 945352. The project that gave rise to these results received the support of a fellowship to M.M.B. from “la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/DI24/12070016. L.V. acknowledges support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI /10.13039/501100011033), the Generalitat de Catalunya through the CERCA programme and to the EMBL partnership. A.R.-F has been supported by the Cris Foundation Excellence Award (PR_EX_2020-24), the ERC Starting Grant MemOriStem (101042992), the Spanish National Research Agency (PID2020-114638RA-I00), the Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322), and the CERCA Program/Generalitat de Catalunya. A.R.-F. acknowledges support from the Institut Catalá de Recerca i Estudis Avançats (ICREA), the American Society of Hematology (ASH) Scholar Award, the Leukemia Lymphoma Society Special Fellow Career Development Program Award (3391–19), the NIH NHLBI K99/R00 transition to independence award (K99 HL146983), the Ministry of Science Ramon y Cajal Fellowship, and the LaCaixa Junior Fellows Incoming Fellowship. C.A.L. is supported by NIH grants P30CA008748 and R00HG012579. L.S.L. acknowledges supported by grants by the German Research Foundation (DFG), including an Emmy Noether fellowship (LU 2336/2-1), LU 2336/3-1, LU 2336/6-1, STA 1586/5-1, TRR241, SFB1588, and the Heinz Maier-Leibnitz Award. N.A.J. was supported by a Medical Research Council and Leukaemia UK Clinical Research Training Fellowship (MR/R002258/1) and MRC DTP Supplementary Funding 2021. P.V. acknowledges funding from the Medical Research Council Molecular Haematology Unit Programme Grant (MC_UU_00029/8), Blood Cancer UK Programme Continuity Grant 13008, NIHR Senior Fellowship, and the Oxford BRC Haematology Theme.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Scherer M, Singh I, Braun MM, Szu-Tu C, Sanchez Sanchez P, Lindenhofer D, et al. Clonal tracing with somatic epimutations reveals dynamics of blood ageing. Nature. 2025 Jul;643(8071):478-87. DOI: 10.1038/s41586-025-09041-8
  • dc.identifier.doi http://dx.doi.org/10.1038/s41586-025-09041-8
  • dc.identifier.issn 0028-0836
  • dc.identifier.uri http://hdl.handle.net/10230/71119
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nature. 2025 Jul;643(8071):478-87
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/945352
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2023-146699NB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101042992
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-114638RA-I00
  • dc.rights © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword Haematopoietic stem cells
  • dc.subject.keyword Methylation analysis
  • dc.title Clonal tracing with somatic epimutations reveals dynamics of blood ageing
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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