Noise-driven cellular heterogeneity in circadian periodicity

Yan Li, Yongli Shan, Ravi V. Desai, Kimberly H. Cox, Leor S. Weinberger, Joseph S. Takahashi

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Nongenetic cellular heterogeneity is associated with aging and disease. However, the origins of cell-to-cell variability are complex and the individual contributions of different factors to total phenotypic variance are still unclear. Here, we took advantage of clear phenotypic heterogeneity of circadian oscillations in clonal cell populations to investigate the underlying mechanisms of cell-to-cell variability. Using a fully automated tracking and analysis pipeline, we examined circadian period length in thousands of single cells and hundreds of clonal cell lines and found that longer circadian period is associated with increased intercellular heterogeneity. Based on our experimental results, we then estimated the contributions of heritable and nonheritable factors to this variation in circadian period length using a variance partitioning model. We found that nonheritable noise predominantly drives intercellular circadian period variation in clonal cell lines, thereby revealing a previously unrecognized link between circadian oscillations and intercellular heterogeneity. Moreover, administration of a noise-enhancing drug reversibly increased both period length and variance. These findings suggest that circadian period may be used as an indicator of cellular noise and drug screening for noise control.

Original languageEnglish (US)
Pages (from-to)10350-10356
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number19
DOIs
StatePublished - May 12 2020

Keywords

  • Circadian oscillation
  • Heterogeneity/ variance
  • Period
  • Single-cell imaging
  • Transcriptional noise

ASJC Scopus subject areas

  • General

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