Molecular Cell
Volume 58, Issue 2, 16 April 2015, Pages 339-352
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Article
Single Mammalian Cells Compensate for Differences in Cellular Volume and DNA Copy Number through Independent Global Transcriptional Mechanisms

https://doi.org/10.1016/j.molcel.2015.03.005Get rights and content
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Highlights

  • Transcription scales with cell volume to maintain transcript concentration

  • Cell fusion shows that increasing cellular content can increase transcription

  • Transcriptional burst size changes with cell volume and burst frequency with cell cycle

  • The burst frequency mechanism allows for proper transcription during early S phase

Summary

Individual mammalian cells exhibit large variability in cellular volume, even with the same absolute DNA content, and so must compensate for differences in DNA concentration in order to maintain constant concentration of gene expression products. Using single-molecule counting and computational image analysis, we show that transcript abundance correlates with cellular volume at the single-cell level due to increased global transcription in larger cells. Cell fusion experiments establish that increased cellular content itself can directly increase transcription. Quantitative analysis shows that this mechanism measures the ratio of cellular volume to DNA content, most likely through sequestration of a transcriptional factor to DNA. Analysis of transcriptional bursts reveals a separate mechanism for gene dosage compensation after DNA replication that enables proper transcriptional output during early and late S phase. Our results provide a framework for quantitatively understanding the relationships among DNA content, cell size, and gene expression variability in single cells.

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