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Memory sequencing reveals heritable single cell gene expression programs associated with distinct cellular behaviors

View ORCID ProfileSydney M. Shaffer, View ORCID ProfileBenjamin L. Emert, Raul Reyes-Hueros, Christopher Coté, Guillaume Harmange, View ORCID ProfileAnn E. Sizemore, Rohit Gupte, View ORCID ProfileEduardo Torre, Abhyudai Singh, View ORCID ProfileDanielle S. Bassett, View ORCID ProfileArjun Raj
doi: https://doi.org/10.1101/379016
Sydney M. Shaffer
1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
2Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania
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  • ORCID record for Sydney M. Shaffer
Benjamin L. Emert
3Perelman School of Medicine, University of Pennsylvania
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Raul Reyes-Hueros
3Perelman School of Medicine, University of Pennsylvania
4Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
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Christopher Coté
2Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania
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Guillaume Harmange
3Perelman School of Medicine, University of Pennsylvania
5Cell and Molecular Biology Group, Perelman School of Medicine, University of Pennsylvania
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Ann E. Sizemore
2Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania
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Rohit Gupte
2Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania
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Eduardo Torre
3Perelman School of Medicine, University of Pennsylvania
4Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
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Abhyudai Singh
6Department of Electrical and Computer Engineering, University of Delaware, Newark, Delaware 19716, USA
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Danielle S. Bassett
2Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania
7Department of Physics & Astronomy, School of Arts and Sciences, University of Pennsylvania
8Department of Electrical & Systems Engineering, School of Engineering and Applied Sciences, University of Pennsylvania
9Department of Neurology, Perelman School of Medicine, University of Pennsylvania
10Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania
11Santa Fe Institute
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Arjun Raj
2Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania
12Department of Genetics, Perelman School of Medicine, University of Pennsylvania
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  • For correspondence: arjunrajlab@gmail.com
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Abstract

Non-genetic factors can cause individual cells to fluctuate substantially in gene expression levels over time. Yet 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 report a method combining Luria and Delbrück’s fluctuation analysis with population-based RNA sequencing (MemorySeq) for identifying genes transcriptome-wide whose fluctuations persist for several cell divisions. MemorySeq revealed multiple gene modules that are expressed together in rare cells within otherwise homogeneous clonal populations. Further, we found that these rare cell subpopulations are associated with biologically distinct behaviors, such as the ability to proliferate in the face of anti-cancer therapeutics, in different cancer cell lines. The identification of non-genetic, multigenerational fluctuations has the potential to reveal new forms of biological memory at the level of single cells and suggests that non-genetic heritability of cellular state may be a quantitative property.

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Posted December 21, 2019.
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Memory sequencing reveals heritable single cell gene expression programs associated with distinct cellular behaviors
Sydney M. Shaffer, Benjamin L. Emert, Raul Reyes-Hueros, Christopher Coté, Guillaume Harmange, Ann E. Sizemore, Rohit Gupte, Eduardo Torre, Abhyudai Singh, Danielle S. Bassett, Arjun Raj
bioRxiv 379016; doi: https://doi.org/10.1101/379016
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Memory sequencing reveals heritable single cell gene expression programs associated with distinct cellular behaviors
Sydney M. Shaffer, Benjamin L. Emert, Raul Reyes-Hueros, Christopher Coté, Guillaume Harmange, Ann E. Sizemore, Rohit Gupte, Eduardo Torre, Abhyudai Singh, Danielle S. Bassett, Arjun Raj
bioRxiv 379016; doi: https://doi.org/10.1101/379016

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