Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Contributions of low molecule number and chromosomal positioning to stochastic gene expression

Nature Genetics volume 37, pages 937–944 (2005)Cite this article

Abstract

The presence of low-copy-number regulators and switch-like signal propagation in regulatory networks are expected to increase noise in cellular processes. We developed a noise amplifier that detects fluctuations in the level of low-abundance mRNAs in yeast. The observed fluctuations are not due to the low number of molecules expressed from a gene per se but originate in the random, rare events of gene activation. The frequency of these events and the correlation between stochastic expressions of genes in a single cell depend on the positioning of the genes along the chromosomes. Transcriptional regulators produced by such random expression propagate noise to their target genes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Synthetic gene circuits for noise amplification and transmission.
Figure 2: Amplification of noise by transcriptional cooperativity.
Figure 3: Input noise measurement using the noise amplifier system.
Figure 4: Dependence of fluctuations on the chromosomal position of PSWI6.
Figure 5: Correlation of fluctuations between the input and output modules.
Figure 6: Noise intensities of cell-cycle promoters.
Figure 7: Model of noise generation.

Similar content being viewed by others

References

  1. Rao, C.V., Wolf, D.M. & Arkin, A.P. Control, exploitation and tolerance of intracellular noise. Nature 420, 231–237 (2002).

    Article  CAS  Google Scholar 

  2. Becskei, A., Seraphin, 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 

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

    Article  Google Scholar 

  4. Erdi, P. & Toth, J. Mathematical Models of Chemical Reactions: Theory and Applications of Deterministic and Stochastic Models (Manchester University Press, Manchester, UK, 1989).

    Google Scholar 

  5. Horsthemke, W., Doering, C.R., Ray, T.S. & Burschka, M.A. Fluctuations and correlations in a diffusion-reaction system - unified description of internal fluctuations and external noise. Phys. Rev. A. 45, 5492–5503 (1992).

    Article  CAS  Google Scholar 

  6. 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  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Pedraza, J.M. & van Oudenaarden, A. Noise propagation in gene networks. Science 307, 1965–1969 (2005).

    Article  CAS  Google Scholar 

  9. 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  CAS  Google Scholar 

  10. Ghaemmaghami, S. et al. Global analysis of protein expression in yeast. Nature 425, 737–741 (2003).

    Article  CAS  Google Scholar 

  11. Holland, M.J. Transcript abundance in yeast varies over six orders of magnitude. J. Biol. Chem. 277, 14363–14366 (2002).

    Article  CAS  Google Scholar 

  12. Velculescu, V.E. et al. Characterization of the yeast transcriptome. Cell 88, 243–251 (1997).

    Article  CAS  Google Scholar 

  13. Swain, P.S. Efficient attenuation of stochasticity in gene expression through post-transcriptional control. J. Mol. Biol. 344, 965–976 (2004).

    Article  CAS  Google Scholar 

  14. Becskei, A., Boselli, M.G. & van Oudenaarden, A. Amplitude control of cell-cycle waves by nuclear import. Nat. Cell Biol. 6, 451–457 (2004).

    Article  CAS  Google Scholar 

  15. Hasty, J., Dolnik, M., Rottschafer, V. & Collins, J.J. Synthetic gene network for entraining and amplifying cellular oscillations. Phys. Rev. Lett. 88, 148101 (2002).

    Article  Google Scholar 

  16. Isaacs, F.J., Hasty, J., Cantor, C.R. & Collins, J.J. Prediction and measurement of an autoregulatory genetic module. Proc. Natl. Acad. Sci. USA 100, 7714–7719 (2003).

    Article  CAS  Google Scholar 

  17. Basu, S., Mehreja, R., Thiberge, S., Chen, M.T. & Weiss, R. Spatiotemporal control of gene expression with pulse-generating networks. Proc. Natl. Acad. Sci. USA 101, 6355–6360 (2004).

    Article  CAS  Google Scholar 

  18. Xiong, W. & Ferrell, J.E., Jr. A positive-feedback-based bistable 'memory module' that governs a cell fate decision. Nature 426, 460–465 (2003).

    Article  CAS  Google Scholar 

  19. Pramila, T., Miles, S., GuhaThakurta, D., Jemiolo, D. & Breeden, L.L. Conserved homeodomain proteins interact with MADS box protein Mcm1 to restrict ECB-dependent transcription to the M/G1 phase of the cell cycle. Genes Dev. 16, 3034–3045 (2002).

    Article  CAS  Google Scholar 

  20. Acar, M., Becskei, A. & van Oudenaarden, A. Enhancement of cellular memory by reducing stochastic transitions. Nature 435, 228–232 (2005).

    Article  CAS  Google Scholar 

  21. Shibata, T. & Fujimoto, K. Noisy signal amplification in ultrasensitive signal transduction. Proc. Natl. Acad. Sci. USA 102, 331–336 (2005).

    Article  CAS  Google Scholar 

  22. Hooshangi, S., Thiberge, S. & Weiss, R. Ultrasensitivity and noise propagation in a synthetic transcriptional cascade. Proc. Natl. Acad. Sci. USA 102, 3581–3586 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Raser, J.M. & O'Shea, E.K. Control of stochasticity in eukaryotic gene expression. Science 304, 1811–1814 (2004).

    Article  CAS  Google Scholar 

  25. Li, G. & Widom, J. Nucleosomes facilitate their own invasion. Nat. Struct. Mol. Biol. 11, 763–769 (2004).

    Article  CAS  Google Scholar 

  26. Vashee, S., Melcher, K., Ding, W.V., Johnston, S.A. & Kodadek, T. Evidence for two modes of cooperative DNA binding in vivo that do not involve direct protein-protein interactions. Curr. Biol. 8, 452–458 (1998).

    Article  CAS  Google Scholar 

  27. Melcher, K. & Xu, H.E. Gal80-Gal80 interaction on adjacent Gal4p binding sites is required for complete GAL gene repression. EMBO J. 20, 841–851 (2001).

    Article  CAS  Google Scholar 

  28. Harbison, C.T. et al. Transcriptional regulatory code of a eukaryotic genome. Nature 431, 99–104 (2004).

    Article  CAS  Google Scholar 

  29. Basehoar, A.D., Zanton, S.J. & Pugh, B.F. Identification and distinct regulation of yeast TATA box-containing genes. Cell 116, 699–709 (2004).

    Article  CAS  Google Scholar 

  30. Maillet, L. et al. Evidence for silencing compartments within the yeast nucleus: a role for telomere proximity and Sir protein concentration in silencer-mediated repression. Genes Dev. 10, 1796–1811 (1996).

    Article  CAS  Google Scholar 

  31. Carr, A.J. & Whitmore, D. Imaging of single light-responsive clock cells reveals fluctuating free-running periods. Nat. Cell Biol. 7, 319–321 (2005).

    Article  CAS  Google Scholar 

  32. Lengronne, A. & Schwob, E. The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G(1). Mol. Cell 9, 1067–1078 (2002).

    Article  CAS  Google Scholar 

  33. Thornton, B.R., Chen, K.C., Cross, F.R., Tyson, J.J. & Toczyski, D.P. Cycling without the cyclosome: modeling a yeast strain lacking the APC. Cell Cycle 3, 629–633 (2004).

    Article  CAS  Google Scholar 

  34. Magee, J.A., Abdulkadir, S.A. & Milbrandt, J. Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation. Cancer Cell 3, 273–283 (2003).

    Article  CAS  Google Scholar 

  35. Sveiczer, A., Csikasz-Nagy, A., Gyorffy, B., Tyson, J.J. & Novak, B. Modeling the fission yeast cell cycle: quantized cycle times in wee1–cdc25Delta mutant cells. Proc. Natl. Acad. Sci. USA 97, 7865–7870 (2000).

    Article  CAS  Google Scholar 

  36. Pirone, J.R. & Elston, T.C. Fluctuations in transcription factor binding can explain the graded and binary responses observed in inducible gene expression. J. Theor. Biol. 226, 111–121 (2004).

    Article  CAS  Google Scholar 

  37. Menon, B.B. et al. Reverse recruitment: The Nup84 nuclear pore subcomplex mediates Rap1/Gcr1/Gcr2 transcriptional activation. Proc. Natl. Acad. Sci. USA 102, 5749–5754 (2005).

    Article  CAS  Google Scholar 

  38. Casolari, J.M. et al. Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell 117, 427–439 (2004).

    Article  CAS  Google Scholar 

  39. Hurst, L.D., Pal, C. & Lercher, M.J. The evolutionary dynamics of eukaryotic gene order. Nat. Rev. Genet. 5, 299–310 (2004).

    Article  CAS  Google Scholar 

  40. Osborne, C.S. et al. Active genes dynamically colocalize to shared sites of ongoing transcription. Nat. Genet. 36, 1065–1071 (2004).

    Article  CAS  Google Scholar 

  41. Struhl, K. Fundamentally different logic of gene regulation in eukaryotes and prokaryotes. Cell 98, 1–4 (1999).

    Article  CAS  Google Scholar 

  42. Martin, D.I. Transcriptional enhancers–on/off gene regulation as an adaptation to silencing in higher eukaryotic nuclei. Trends Genet. 17, 444–448 (2001).

    Article  CAS  Google Scholar 

  43. Ahmad, K. & Henikoff, S. Modulation of a transcription factor counteracts heterochromatic gene silencing in Drosophila. Cell 104, 839–847 (2001).

    Article  CAS  Google Scholar 

  44. Misteli, T. Concepts in nuclear architecture. Bioessays 27, 477–487 (2005).

    Article  CAS  Google Scholar 

  45. Roix, J.J., McQueen, P.G., Munson, P.J., Parada, L.A. & Misteli, T. Spatial proximity of translocation-prone gene loci in human lymphomas. Nat. Genet. 34, 287–291 (2003).

    Article  CAS  Google Scholar 

  46. Dernburg, A.F. et al. Perturbation of nuclear architecture by long-distance chromosome interactions. Cell 85, 745–759 (1996).

    Article  CAS  Google Scholar 

  47. Nutt, S.L. et al. Independent regulation of the two Pax5 alleles during B-cell development. Nat. Genet. 21, 390–395 (1999).

    Article  CAS  Google Scholar 

  48. Peccoud, J. & Ycard, B. Markovian modelling of gene product synthesis. Theor. Popul. Biol. 48, 222–234 (1995).

    Article  Google Scholar 

  49. Iyer, V. & Struhl, K. Absolute mRNA levels and transcriptional initiation rates in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 93, 5208–5212 (1996).

    Article  CAS  Google Scholar 

  50. Guptasarma, P. Does replication-induced transcription regulate synthesis of the myriad low copy number proteins of Escherichia coli?. Bioessays 17, 987–997 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Pedraza, W. Tansey and M. Thattai for discussions. A.B. is a Long Term Fellow of the Human Frontier Science Program. This work was supported by a grant from the US National Institutes of Health and a US National Science Foundation CAREER grant.

Author information

Authors and Affiliations

  1. Department of Physics, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Attila Becskei, Benjamin B Kaufmann & Alexander van Oudenaarden

  2. Division of Engineering and Applied Sciences, Harvard University, Cambridge, 02138, Massachusetts, USA

    Benjamin B Kaufmann

Authors
  1. Attila Becskei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benjamin B Kaufmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander van Oudenaarden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander van Oudenaarden.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Moments of distribution of YFP fluorescence. (PDF 91 kb)

Supplementary Fig. 2

Fitting of the input noise. (PDF 134 kb)

Supplementary Table 1

Yeast strains. (PDF 115 kb)

Supplementary Note (PDF 202 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Becskei, A., Kaufmann, B. & van Oudenaarden, A. Contributions of low molecule number and chromosomal positioning to stochastic gene expression. Nat Genet 37, 937–944 (2005). https://doi.org/10.1038/ng1616

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1616

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing