Cell
Volume 182, Issue 4, 20 August 2020, Pages 947-959.e17
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Article
Memory Sequencing Reveals Heritable Single-Cell Gene Expression Programs Associated with Distinct Cellular Behaviors

https://doi.org/10.1016/j.cell.2020.07.003Get rights and content
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Highlights

  • MemorySeq identifies slowly fluctuating gene expression states in rare single cells

  • Slowly fluctuating states are associated with drug resistance in cancer

  • MemorySeq reveals broad patterns of gene co-expression in rare cells

Summary

Non-genetic factors can cause individual cells to fluctuate substantially in gene expression levels over time. It remains unclear whether these fluctuations can persist for much longer than the time of one cell division. Current methods for measuring gene expression in single cells mostly rely on single time point measurements, making the duration of gene expression fluctuations or cellular memory difficult to measure. Here, we combined Luria and Delbrück’s fluctuation analysis with population-based RNA sequencing (MemorySeq) for identifying genes transcriptome-wide whose fluctuations persist for several divisions. MemorySeq revealed multiple gene modules that expressed together in rare cells within otherwise homogeneous clonal populations. These rare cell subpopulations were associated with biologically distinct behaviors like proliferation in the face of anti-cancer therapeutics. The identification of non-genetic, multigenerational fluctuations can reveal new forms of biological memory in single cells and suggests that non-genetic heritability of cellular state may be a quantitative property.

Keywords

single-cell
gene expression memory
cancer drug resistance

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These authors contributed equally

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