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Noise in eukaryotic gene expression

Nature volume 422, pages 633–637 (2003)Cite this article

Abstract

Transcription in eukaryotic cells has been described as quantal1, with pulses of messenger RNA produced in a probabilistic manner2,3. This description reflects the inherently stochastic nature4,5,6,7,8,9 of gene expression, known to be a major factor in the heterogeneous response of individual cells within a clonal population to an inducing stimulus10,11,12,13,14,15,16. Here we show in Saccharomyces cerevisiae that stochasticity (noise) arising from transcription contributes significantly to the level of heterogeneity within a eukaryotic clonal population, in contrast to observations in prokaryotes15, and that such noise can be modulated at the translational level. We use a stochastic model of transcription initiation specific to eukaryotes to show that pulsatile mRNA production, through reinitiation, is crucial for the dependence of noise on transcriptional efficiency, highlighting a key difference between eukaryotic and prokaryotic sources of noise. Furthermore, we explore the propagation of noise in a gene cascade network and demonstrate experimentally that increased noise in the transcription of a regulatory protein leads to increased cell–cell variability in the target gene output, resulting in prolonged bistable expression states. This result has implications for the role of noise in phenotypic variation and cellular differentiation.

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Figure 1: Transcriptional control of PGAL1*.
Figure 2: Effect of transcriptional and translational efficiency on noise strength.
Figure 3: Simulations of eukaryotic gene expression noise.
Figure 4: Cascading noise in a gene network and effect on cellular response.

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Acknowledgements

We thank T. Gilmore for guidance and helpful advice on switch construction, F. Isaacs for helpful discussions and advice, and B. Cormack for the gift of pEGFP3. This work was supported by DARPA, NSF and the Danish Research Agency.

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Author notes

  1. Correspondence and requests for materials should be addressed to J.J.C.

  2. William J. Blake and Mads KÆrn: These authors contributed equally to this work

Authors and Affiliations

  1. Center for BioDynamics, Center for Advanced Biotechnology, Bioinformatics Program, and Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, Massachusetts, 02215, USA

    William J. Blake, Mads KÆrn, Charles R. Cantor & J. J. Collins

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  1. William J. Blake
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  2. Mads KÆrn
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Correspondence to J. J. Collins.

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Blake, W., KÆrn, M., Cantor, C. et al. Noise in eukaryotic gene expression. Nature 422, 633–637 (2003). https://doi.org/10.1038/nature01546

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