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Mol Cell. 2015 Apr 16;58(2):339-52. doi: 10.1016/j.molcel.2015.03.005. Epub 2015 Apr 9.

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

Author information

1
Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
4
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
6
Department of Electrical and Computer Engineering, University of Delaware, Newark, DE 19716, USA.
7
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: rajlaboratory@gmail.com.

Abstract

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.

PMID:
25866248
PMCID:
PMC4402149
DOI:
10.1016/j.molcel.2015.03.005
[Indexed for MEDLINE]
Free PMC Article

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