Noise in eukaryotic gene expression (original) (raw)
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- Published: 10 April 2003
Nature volume 422, pages 633–637 (2003)Cite this article
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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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References
- Hume, D. A. Probability in transcriptional regulation and its implications for leukocyte differentiation and inducible gene expression. Blood 96, 2323–2328 (2000)
CAS PubMed Google Scholar - Ross, I. L., Browne, C. M. & Hume, D. A. Transcription of individual genes in eukaryotic cells occurs randomly and infrequently. Immunol. Cell Biol. 72, 177–185 (1994)
Article CAS Google Scholar - Walters, M. C. et al. Enhancers increase the probability but not the level of gene expression. Proc. Natl Acad. Sci. USA 92, 7125–7129 (1995)
Article ADS CAS Google Scholar - Ko, M. S. H. A stochastic model for gene induction. J. Theor. Biol. 153, 181–194 (1991)
Article CAS Google Scholar - McAdams, H. H. & Arkin, A. Stochastic mechanisms in gene expression. Proc. Natl Acad. Sci. USA 94, 814–819 (1997)
Article ADS CAS Google Scholar - Hasty, J., Pradines, J., Dolnik, M. & Collins, J. J. Noise-based switches and amplifiers for gene expression. Proc. Natl Acad. Sci. USA 97, 2075–2080 (2000)
Article ADS CAS Google Scholar - Thattai, M. & van Oudenaarden, A. Intrinsic noise in gene regulatory networks. Proc. Natl Acad. Sci. USA 98, 8614–8619 (2001)
Article ADS CAS Google Scholar - Kepler, T. B. & Elston, T. C. Stochasticity in transcriptional regulation: origins, consequences, and mathematical representations. Biophys. J. 81, 3116–3136 (2001)
Article ADS CAS Google Scholar - Swain, P. S., Elowitz, M. B. & Siggia, E. D. Intrinsic and extrinsic contributions to stochasticity in gene expression. Proc. Natl Acad. Sci. USA 99, 12795–12800 (2002)
Article ADS CAS Google Scholar - Novick, A. & Weiner, M. Enzyme induction as an all-or-none phenomenon. Proc. Natl Acad. Sci. USA 43, 553–566 (1957)
Article ADS CAS Google Scholar - Ko, M. S. H., Nakauchi, H. & Takahashi, N. The dose dependence of glucocorticoid-inducible gene expression results from changes in the number of transcriptionally active templates. EMBO J. 9, 2835–2842 (1990)
Article CAS Google Scholar - Fiering, S. et al. Single cell assay of a transcription factor reveals a threshold in transcription activated by signals emanating from the T-cell antigen receptor. Genes Dev. 4, 1823–1834 (1990)
Article CAS Google Scholar - van Roon, M. A., Aten, J. A., van Oven, C. H., Charles, R. & Lamers, W. H. The initiation of hepatocyte-specific gene expression within embryonic hepatocytes is a stochastic event. Dev. Biol. 136, 508–516 (1989)
Article CAS Google Scholar - Becskei, A., Séraphin, B. & Serrano, L. Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion. EMBO J. 20, 2528–2535 (2001)
Article CAS Google Scholar - Ozbudak, E. M., Thattai, M., Kurtser, I., Grossman, A. D. & van Oudenaarden, A. Regulation of noise in the expression of a single gene. Nature Genet. 31, 69–73 (2002)
Article CAS Google Scholar - Elowitz, M. B., Levine, A. J., Siggia, E. D. & Swain, P. S. Stochastic gene expression in a single cell. Science 297, 1183–1186 (2002)
Article ADS CAS Google Scholar - Ptashne, M. & Gann, A. Transcriptional activation by recruitment. Nature 386, 569–577 (1997)
Article ADS CAS Google Scholar - Bhaumik, S. R. & Green, M. R. SAGA is an essential in vivo target of the yeast acidic activator Gal4p. Genes Dev. 15, 1935–1945 (2001)
Article CAS Google Scholar - Larschan, E. & Winston, F. The S. cerevisiae SAGA complex functions in vivo as a coactivator for transcriptional activation by Gal4. Genes Dev. 15, 1946–1956 (2001)
Article CAS Google Scholar - Rossi, F. M. V., Kringstein, A. M., Spicher, A., Guicherit, O. M. & Blau, H. M. Transcriptional control: rheostat converted to on/off switch. Mol. Cell 6, 723–728 (2000)
Article CAS Google Scholar - Biggar, S. R. & Crabtree, G. R. Cell signaling can direct either binary or graded transcriptional responses. EMBO J. 20, 3167–3176 (2001)
Article CAS Google Scholar - Chatterjee, S. & Struhl, K. Connecting a promoter-bound protein to TBP bypasses the need for a transcriptional activation domain. Nature 374, 820–822 (1995)
Article ADS CAS Google Scholar - Klages, N. & Strubin, M. Stimulation of RNA polymerase II transcription initiation by recruitment of TBP in vivo. Nature 374, 822–823 (1995)
Article ADS CAS Google Scholar - Struhl, K. Chromatin structure and RNA polymerase II connection: implications for transcription. Cell 84, 179–182 (1996)
Article CAS Google Scholar - Hahn, S. Activation and the role of reinitiation in the control of transcription by RNA polymerase II. Cold Spring Harb. Symp. Quant. Biol. 63, 181–188 (1998)
Article CAS Google Scholar - Sharp, P. M. & Li, W. H. The codon adaptation index—a measure of directional synonymous codon usage bias, and its potential applications. Nucleic Acids Res. 15, 1281–1295 (1987)
Article ADS CAS Google Scholar - Thattai, M. & van Oudenaarden, A. Attenuation of noise in ultrasensitive signaling cascades. Biophys. J. 82, 2943–2950 (2002)
Article CAS Google Scholar - Kemkemer, R., Schrank, S., Vogel, W., Gruler, H. & Kaufmann, D. Increased noise as an effect of haploinsufficiency of the tumour-suppressor gene neurofibromatosis type 1 in vitro. Proc. Natl Acad. Sci. USA 99, 13783–13788 (2002)
Article ADS CAS Google Scholar - Stewart, J. J. & Stargell, L. A. The stability of the TFIIA-TBP-DNA complex is dependent on the sequence of the TATAAA element. J. Biol. Chem. 276, 30078–30084 (2001)
Article CAS Google Scholar - Yean, D. & Gralla, J. Transcription reinitiation rate: a special role for the TATA box. Mol. Cell. Biol. 17, 3809–3816 (1997)
Article CAS Google Scholar
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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- Correspondence and requests for materials should be addressed to J.J.C.
- William J. Blake and Mads KÆrn: These authors contributed equally to this work
Authors and Affiliations
- 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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- William J. Blake
You can also search for this author inPubMed Google Scholar - Mads KÆrn
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Correspondence toJ. 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
- Received: 20 December 2002
- Accepted: 07 March 2003
- Issue Date: 10 April 2003
- DOI: https://doi.org/10.1038/nature01546
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