Multigenerational cell tracking of DNA replication and heritable DNA damage

Andreas Panagopoulos, Merula Stout, Sinan Kilic, Peter Leary, Julia Vornberger, Virginia Pasti, Antonio Galarreta, Aleksandra Lezaja, Kyra Kirschenbühler, Ralph Imhof, Hubert Rehrauer, Urs Ziegler and Matthias Altmeyer ()
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Andreas Panagopoulos: University of Zurich
Merula Stout: University of Zurich
Sinan Kilic: University of Zurich
Peter Leary: ETH Zurich and University of Zurich
Julia Vornberger: University of Zurich
Virginia Pasti: University of Zurich
Antonio Galarreta: University of Zurich
Aleksandra Lezaja: University of Zurich
Kyra Kirschenbühler: University of Zurich
Ralph Imhof: University of Zurich
Hubert Rehrauer: ETH Zurich and University of Zurich
Urs Ziegler: University of Zurich
Matthias Altmeyer: University of Zurich

Nature, 2025, vol. 642, issue 8068, 785-795

Abstract: Abstract Cell heterogeneity is a universal feature of life. Although biological processes affected by cell-to-cell variation are manifold, from developmental plasticity to tumour heterogeneity and differential drug responses, the sources of cell heterogeneity remain largely unclear1,2. Mutational and epigenetic signatures from cancer (epi)genomics are powerful for deducing processes that shaped cancer genome evolution3–5. However, retrospective analyses face difficulties in resolving how cellular heterogeneity emerges and is propagated to subsequent cell generations. Here, we used multigenerational single-cell tracking based on endogenously labelled proteins and custom-designed computational tools to elucidate how oncogenic perturbations induce sister cell asymmetry and phenotypic heterogeneity. Dual CRISPR-based genome editing enabled simultaneous tracking of DNA replication patterns and heritable endogenous DNA lesions. Cell lineage trees of up to four generations were tracked in asynchronously growing cells, and time-resolved lineage analyses were combined with end-point measurements of cell cycle and DNA damage markers through iterative staining. Besides revealing replication and repair dynamics, damage inheritance and emergence of sister cell heterogeneity across multiple cell generations, through combination with single-cell transcriptomics, we delineate how common oncogenic events trigger multiple routes towards polyploidization with distinct outcomes for genome integrity. Our study provides a framework to dissect phenotypic plasticity at the single-cell level and sheds light onto cellular processes that may resemble early events during cancer development.

Date: 2025
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DOI: 10.1038/s41586-025-08986-0

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