Single mammalian cells compensate for differences in cellular volume and DNA copy number through independent global transcriptional mechanisms

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...

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Bibliographic Details
Published in:Molecular cell 2015-04, Vol.58 (2), p.339-352
Main Authors: Padovan-Merhar, Olivia, Nair, Gautham P., Biaesch, Andrew, Mayer, Andreas, Scarfone, Steven, Foley, Shawn W., Wu, Angela R., Churchman, L. Stirling, Singh, Abhyudai, Raj, Arjun
Format: Article
Language:English
Subjects:
Animals
Caenorhabditis elegans - genetics
Cells, Cultured
Fibroblasts - cytology
Foreskin - cytology
Gene Dosage
Gene Expression
Humans
In Situ Hybridization, Fluorescence - methods
Male
Molecular Sequence Data
S Phase
Sequence Analysis, RNA - methods
Single-Cell Analysis - methods
Transcription, Genetic
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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, mostly 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 between DNA content, cell size and gene expression variability in single cells. [Display omitted]
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2015.03.005