巴塞罗那科技学院Lars Velten小组的一项最新研究报道了体细胞克隆示踪揭示了血液老化的动力学。2025年5月21日出版的《自然》杂志发表了这项成果。
在这里，课题组人员发现CpG位点的一个子集的DNA甲基化反映了细胞分化，而另一个子集经历随机变异，可以作为克隆身份的数字条形码。该研究组证明了在单CpG分辨率下靶向DNA甲基化的单细胞分析可以准确地提取两层信息。为此，研究小组开发了EPI-Clone，一种大规模的无转基因谱系追踪方法。应用于单核细胞和人类造血，研究团队在数十个个体和230,358个单细胞中捕获了数百个克隆分化轨迹。在单主题衰老中，该研究组证明了骨髓偏倚和老年造血干细胞的低输出仅限于少数扩增克隆，而许多功能年轻的克隆在老年时持续存在。在人类衰老过程中，有或没有已知克隆造血驱动突变的克隆7是与年龄相关的克隆扩增谱的一部分，表现出类似的谱系偏见。EPI-Clone能够在大规模的造血细胞状态景观上精确和无转基因的单细胞谱系追踪。
据介绍，目前以通过分化跟踪干细胞克隆为主题的方法需要基因工程或依赖稀疏的体细胞DNA变体，这限制了它们的广泛应用。
附：英文原文
Title: Clonal tracing with somatic epimutations reveals dynamics of blood ageing
Author: Scherer, Michael, Singh, Indranil, Braun, Martina Maria, Szu-Tu, Chelsea, Sanchez Sanchez, Pedro, Lindenhofer, Dominik, Jakobsen, Niels Asger, Krber, Verena, Kardorff, Michael, Nitsch, Lena, Kautz, Pauline, Rhle, Julia, Bianchi, Agostina, Cozzuto, Luca, Frmel, Robert, Beneyto-Calabuig, Sergi, Lareau, Caleb, Satpathy, Ansuman T., Beekman, Rene, Steinmetz, Lars M., Raffel, Simon, Ludwig, Leif S., Vyas, Paresh, Rodriguez-Fraticelli, Alejo, Velten, Lars
Issue&Volume: 2025-05-21
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.
DOI: 10.1038/s41586-025-09041-8
Source: https://www.nature.com/articles/s41586-025-09041-8