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Functional roles for noise in genetic circuits

Nature volume 467, pages 167–173 (2010)Cite this article

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Abstract

The genetic circuits that regulate cellular functions are subject to stochastic fluctuations, or ‘noise’, in the levels of their components. Noise, far from just a nuisance, has begun to be appreciated for its essential role in key cellular activities. Noise functions in both microbial and eukaryotic cells, in multicellular development, and in evolution. It enables coordination of gene expression across large regulons, as well as probabilistic differentiation strategies that function across cell populations. At the longest timescales, noise may facilitate evolutionary transitions. Here we review examples and emerging principles that connect noise, the architecture of the gene circuits in which it is present, and the biological functions it enables. We further indicate some of the important challenges and opportunities going forward.

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Figure 1: Gene expression noise is ubiquitous, and affects diverse systems at several levels.
Figure 2: Frequency modulation of stochastic nuclear localization bursts enables coordination of gene regulation.
Figure 3: Probabilistic differentiation.
Figure 4: Roles of noise in evolution.

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References

  1. Maheshri, N. & O’Shea, E. K. Living with noisy genes: how cells function reliably with inherent variability in gene expression. Annu. Rev. Biophys. Biomol. Struct. 36, 413–434 (2007)

    Article  CAS  PubMed  Google Scholar 

  2. Raj, A. & van Oudenaarden, A. Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135, 216–226 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Locke, J. & Elowitz, M. Using movies to analyse gene circuit dynamics in single cells. Nature Rev. Microbiol. 7, 383–392 (2009)

    Article  CAS  Google Scholar 

  4. Davidson, C. & Surette, M. Individuality in bacteria. Annu. Rev. Genet. 42, 253–268 (2008)

    Article  CAS  PubMed  Google Scholar 

  5. Losick, R. & Desplan, C. Stochasticity and cell fate. Science 320, 65–68 (2008)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lestas, I., Vinnicombe, G. & Paulsson, J. Fundamental limits on the suppression of molecular fluctuations. Nature 10.1038/nature09333 (this issue)

  7. McAdams, H. H. & Arkin, A. Stochastic mechanisms in gene expression. Proc. Natl Acad. Sci. USA 94, 814–819 (1997)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Friedman, N., Cai, L. & Xie, X. Linking stochastic dynamics to population distribution: an analytical framework of gene expression. Phys. Rev. Lett. 97, 168302 (2006)

    Article  ADS  PubMed  Google Scholar 

  9. Paulsson, J. Summing up the noise in gene networks. Nature 427, 415–418 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Paulsson, J., Berg, O. & Ehrenberg, M. Stochastic focusing: fluctuation-enhanced sensitivity of intracellular regulation. Proc. Natl Acad. Sci. USA 97, 7148 (2000)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Golding, I., Paulsson, J., Zawilski, S. M. & Cox, E. C. Real-time kinetics of gene activity in individual bacteria. Cell 123, 1025–1036 (2005)

    Article  CAS  PubMed  Google Scholar 

  12. Yu, J., Xiao, J., Ren, X., Lao, K. & Xie, X. S. Probing gene expression in live cells, one protein molecule at a time. Science 311, 1600–1603 (2006)

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Cai, L., Friedman, N. & Xie, X. S. Stochastic protein expression in individual cells at the single molecule level. Nature 440, 358–362 (2006)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. 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  PubMed  Google Scholar 

  15. Zenklusen, D., Larson, D. R. & Singer, R. H. Single-RNA counting reveals alternative modes of gene expression in yeast. Nature Struct. Mol. Biol. 15, 1263–1271 (2008)

    Article  CAS  Google Scholar 

  16. Blake, W. J., KÆrn, M., Cantor, C. R. & Collins, J. J. Noise in eukaryotic gene expression. Nature 422, 633–637 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Raj, A., Peskin, C., Tranchina, D., Vargas, D. & Tyagi, S. Stochastic mRNA synthesis in mammalian cells. PLoS Biol. 4, e309 (2006)

    Article  PubMed  PubMed Central  Google Scholar 

  18. Paré, A. et al. Visualization of individual Scr mRNAs during Drosophila embryogenesis yields evidence for transcriptional bursting. Curr. Biol. 19, 2037–2042 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  19. Dunlop, M., Cox, R., III, Levine, J., Murray, R. & Elowitz, M. Regulatory activity revealed by dynamic correlations in gene expression noise. Nature Genet. 40, 1493–1498 (2008)

    Article  CAS  PubMed  Google Scholar 

  20. Cox, C., McCollum, J., Allen, M., Dar, R. & Simpson, M. Using noise to probe and characterize gene circuits. Proc. Natl Acad. Sci. USA 105, 10809–10814 (2008)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rosenfeld, N., Young, J. W., Alon, U., Swain, P. S. & Elowitz, M. B. Gene regulation at the single-cell level. Science 307, 1962–1965 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Sigal, A. et al. Variability and memory of protein levels in human cells. Nature 444, 643–646 (2006)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. 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  PubMed  Google Scholar 

  24. Bar-Even, A. et al. Noise in protein expression scales with natural protein abundance. Nature Genet. 38, 636–643 (2006)

    Article  CAS  PubMed  Google Scholar 

  25. Newman, J. et al. Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise. Nature 441, 840–846 (2006)

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Cai, L., Dalal, C. K. & Elowitz, M. B. Frequency-modulated nuclear localization bursts coordinate gene regulation. Nature 455, 485–490 (2008)This paper reports that the yeast calcium-response system uses frequency modulation of stochastic nuclear localization bursts of the Crz1 transcription factor to enable coordination (proportional expression) across large regulons.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cyert, M. Genetic analysis of calmodulin and its targets in Saccharomyces cerevisiae . Annu. Rev. Genet. 35, 647–672 (2001)

    Article  CAS  PubMed  Google Scholar 

  28. Shankaran, H. et al. Rapid and sustained nuclear–cytoplasmic ERK oscillations induced by epidermal growth factor. Mol. Syst. Biol. 5 332 10.1038/msb.2009.90 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Thattai, M. & van Oudenaarden, A. Stochastic gene expression in fluctuating environments. Genetics 167, 523–530 (2004)

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kussell, E. & Leibler, S. Phenotypic diversity, population growth, and information in fluctuating environments. Science 309, 2075–2078 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  31. Wolf, D., Vazirani, V. & Arkin, A. Diversity in times of adversity: probabilistic strategies in microbial survival games. J. Theor. Biol. 234, 227–253 (2005)

    Article  MathSciNet  PubMed  Google Scholar 

  32. Acar, M., Mettetal, J. T. & van Oudenaarden, A. Stochastic switching as a survival strategy in fluctuating environments. Nature Genet. 40, 471–475 (2008)A synthetic study demonstrating that the rate of stochastic switching between phenotypic states is optimized when it matches the rate of environmental fluctuations.

    Article  CAS  PubMed  Google Scholar 

  33. Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L. & Leibler, S. Bacterial persistence as a phenotypic switch. Science 305, 1622–1625 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  34. Gardner, T. S., Cantor, C. R. & Collins, J. J. Construction of a genetic toggle switch in Escherichia coli . Nature 403, 339–342 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  35. Kashiwagi, A., Urabe, I., Kaneko, K. & Yomo, T. Adaptive response of a gene network to environmental changes by fitness-induced attractor selection. PLoS ONE 1, e49 (2006)

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  36. To, T. & Maheshri, N. Noise can induce bimodality in positive transcriptional feedback loops without bistability. Science 327, 1142 (2010)

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Novick, A. & Weiner, M. Enzyme induction as an all-or-none phenomenon. Proc. Natl Acad. Sci. USA 43, 553–566 (1957)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. Benzer, S. Induced synthesis of enzymes in bacteria analyzed at the cellular level. Biochim. Biophys. Acta 11, 383–395 (1953)

    Article  CAS  PubMed  Google Scholar 

  39. Ozbudak, E. M., Thattai, M., Lim, H. N., Shraiman, B. I. & Van Oudenaarden, A. Multistability in the lactose utilization network of Escherichia coli . Nature 427, 737–740 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  40. Choi, P. J., Cai, L., Frieda, K. & Xie, X. S. A stochastic single-molecule event triggers phenotype switching of a bacterial cell. Science 322, 442–446 (2008)This detailed analysis of stochastic state transitions in the lac operon identified stochastic promoter state switching as the origin of phenotypic changes in E. coli.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. Elf, J., Li, G. W. & Xie, X. S. Probing transcription factor dynamics at the single-molecule level in a living cell. Science 316, 1191–1194 (2007)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  42. Boeger, H., Griesenbeck, J. & Kornberg, R. D. Nucleosome retention and the stochastic nature of promoter chromatin remodeling for transcription. Cell 133, 716–726 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Degenhardt, T. et al. Population-level transcription cycles derive from stochastic timing of single-cell transcription. Cell 138, 489–501 (2009)

    Article  CAS  PubMed  Google Scholar 

  44. Sharma, S. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010)A small sub-population resists drug treatment with no genetic variability. Specific inhibitors eliminate the resistant sub-population while keeping the larger sensitive population.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Maamar, H. & Dubnau, D. Bistability in the Bacillus subtilis K-state (competence) system requires a positive feedback loop. Mol. Microbiol. 56, 615–624 (2005)

    Article  CAS  PubMed  Google Scholar 

  46. Süel, G. M., Garcia-Ojalvo, J., Liberman, L. M. & Elowitz, M. B. An excitable gene regulatory circuit induces transient cellular differentiation. Nature 440, 545–550 (2006)

    Article  ADS  PubMed  Google Scholar 

  47. Süel, G. M., Kulkarni, R. P., Dworkin, J., Garcia-Ojalvo, J. & Elowitz, M. B. Tunability and noise dependence in differentiation dynamics. Science 315, 1716–1719 (2007)

    Article  ADS  PubMed  Google Scholar 

  48. Maamar, H., Raj, A. & Dubnau, D. Noise in gene expression determines cell fate in Bacillus subtilis . Science 317, 526–529 (2007)By reciprocally perturbing transcription and translation rates, the authors showed that noise in the expression of a master transcription factor directly regulates the frequency of differentiation into the competent state.

    Article  ADS  CAS  PubMed  Google Scholar 

  49. Di Talia, S., Skotheim, J., Bean, J., Siggia, E. & Cross, F. The effects of molecular noise and size control on variability in the budding yeast cell cycle. Nature 448, 947–951 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  50. Çağatay, T., Turcotte, M., Elowitz, M., Garcia-Ojalvo, J. & Süel, G. M. Architecture-dependent noise discriminates functionally analogous differentiation circuits. Cell 139, 512–522 (2009)Two seemingly equivalent architectures for the competence transient differentiation system differ principally in their variability, with the wild-type version more sensitive to noise, enhancing the range of environments in which the system can function.

    Article  PubMed  Google Scholar 

  51. Veening, J. W. et al. Bet-hedging and epigenetic inheritance in bacterial cell development. Proc. Natl Acad. Sci. USA 105, 4393–4398 (2008)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fujita, M. & Losick, R. Evidence that entry into sporulation in Bacillus subtilis is governed by a gradual increase in the level and activity of the master regulator Spo0A. Genes Dev. 19, 2236–2244 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nachman, I., Regev, A. & Ramanathan, S. Dissecting timing variability in yeast meiosis. Cell 131, 544–556 (2007)

    Article  CAS  PubMed  Google Scholar 

  54. Spencer, S. L., Gaudet, S., Albeck, J. G., Burke, J. M. & Sorger, P. K. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459, 428–432 (2009)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. Suda, T., Suda, J. & Ogawa, M. Single-cell origin of mouse hemopoietic colonies expressing multiple lineages in variable combinations. Proc. Natl Acad. Sci. USA 80, 6689 (1983)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  56. Shah, N., Groves, A. & Anderson, D. Alternative neural crest cell fates are instructively promoted by TGFβ superfamily members. Cell 85, 331–343 (1996)

    Article  CAS  PubMed  Google Scholar 

  57. Chazaud, C., Yamanaka, Y., Pawson, T. & Rossant, J. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev. Cell 10, 615–624 (2006)

    Article  CAS  PubMed  Google Scholar 

  58. Dietrich, J. E. & Hiiragi, T. Stochastic patterning in the mouse pre-implantation embryo. Development 134, 4219–4231 (2007)

    Article  CAS  PubMed  Google Scholar 

  59. Yamanaka, Y., Lanner, F. & Rossant, J. FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development 137, 715–724 (2010)

    Article  CAS  PubMed  Google Scholar 

  60. Morris, S. A. et al. Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo. Proc. Natl Acad. Sci. USA 107, 6364–6369 (2010)The above two references show that differentiation in the early mouse embryo seems to occur through a stochastic process with a lineage bias, supporting the stochastic sorting model of patterning.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kay, R. R. & Thompson, C. R. L. Forming patterns in development without morphogen gradients: scattered differentiation and sorting out. Cold Spring Harb. Perspect. Biol. 1 10.1101/cshperspect.a001503 (2009)

  62. Singh, A. M., Hamazaki, T., Hankowski, K. E. & Terada, N. A heterogeneous expression pattern for Nanog in embryonic stem cells. Stem Cells 25, 2534–2542 (2007)

    Article  CAS  PubMed  Google Scholar 

  63. Chambers, I. et al. Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230–1234 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  64. Kalmar, T. et al. Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol. 7, e1000149 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  65. Chang, H., Hemberg, M., Barahona, M., Ingber, D. & Huang, S. Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453, 544 (2008)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  66. Canham, M. A., Sharov, A. A., Ko, M. S. H. & Brickman, J. M. Functional heterogeneity of embryonic stem cells revealed through translational amplification of an early endodermal transcript. PLoS Biol. 8, e1000379 (2010)

    Article  PubMed  PubMed Central  Google Scholar 

  67. Hill, W. & Zhang, X. Effects on phenotypic variability of directional selection arising through genetic differences in residual variability. Genet. Res. 83, 121–132 (2004)

    Article  CAS  PubMed  Google Scholar 

  68. Ito, Y., Toyota, H., Kaneko, K. & Yomo, T. How selection affects phenotypic fluctuation. Mol. Syst. Biol. 5 10.1038/msb.2009.23 (2009)

  69. Raj, A., Rifkin, S., Andersen, E. & van Oudenaarden, A. Variability in gene expression underlies incomplete penetrance. Nature 463, 913–918 (2010)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  70. Queitsch, C., Sangster, T. A. & Lindquist, S. Hsp90 as a capacitor of phenotypic variation. Nature 417, 618–624 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  71. Eldar, A. et al. Partial penetrance facilitates developmental evolution in bacteria. Nature 460, 510–514 (2009)Single-cell analysis of a bacterial developmental pathway reveals how new morphologies can be produced at low penetrance and then stabilized by additional mutations, providing a gradual pathway for discrete evolutionary transitions.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  72. Angert, E. R. Alternatives to binary fission in bacteria. Nature Rev. Microbiol. 3, 214–224 (2005)

    Article  CAS  Google Scholar 

  73. Mehta, P., Goyal, S. & Wingreen, N. A quantitative comparison of sRNA-based and protein-based gene regulation. Mol. Syst. Biol. 4 10.1038/msb.2008.58 (2008)

  74. Levine, E., Zhang, Z., Kuhlman, T. & Hwa, T. Quantitative characteristics of gene regulation by small RNA. PLoS Biol. 5, e229 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  75. Valdeolmillos, M., Gomis, A. & Sanchez-Andres, J. In vivo synchronous membrane potential oscillations in mouse pancreatic β-cells: lack of co-ordination between islets. J. Physiol. (Lond.) 493, 9–15 (1996)

    Article  CAS  Google Scholar 

  76. Tang, F. et al. mRNA-Seq whole-transcriptome analysis of a single cell. Nature Methods 6, 377–382 (2009)

    Article  CAS  PubMed  Google Scholar 

  77. Beaumont, H., Gallie, J., Kost, C., Ferguson, G. & Rainey, P. Experimental evolution of bet hedging. Nature 462, 90–93 (2009)

    Article  ADS  CAS  PubMed  Google Scholar 

  78. Snijder, B. et al. Population context determines cell-to-cell variability in endocytosis and virus infection. Nature 461, 520–523 (2009)

    Article  ADS  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank G. Süel, A. Raj, F. Tan and J. Rossant for providing images. We thank N. Wingreen, D. J. Anderson, R. Kishony, J.-G. Ojalvo, G. Süel, H. Y. Kueh and members of the Elowitz laboratory for discussions. Work in M.B.E.’s laboratory was supported by NIH grants R01GM079771, P50 GM068763, NSF CAREER Award 0644463 and the Packard Foundation. A.E. was supported by EMBO, the International Human Frontier Science Organization and a Baxter fellowship.

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  1. Avigdor Eldar

    Present address: Present address: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv 69978, Israel.,

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  1. Howard Hughes Medical Institute, Caltech M/C 114-96, 1200 East California Boulevard, Pasadena, California 91125, USA ,

    Avigdor Eldar & Michael B. Elowitz

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Eldar, A., Elowitz, M. Functional roles for noise in genetic circuits. Nature 467, 167–173 (2010). https://doi.org/10.1038/nature09326

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