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.

A Polycomb-based switch underlying quantitative epigenetic memory

Abstract

The conserved Polycomb repressive complex 2 (PRC2) generates trimethylation of histone 3 lysine 27 (H3K27me3)1,2, a modification associated with stable epigenetic silencing3,4. Much is known about PRC2-induced silencing but key questions remain concerning its nucleation and stability. Vernalization, the perception and memory of winter in plants, is a classic epigenetic process that, in Arabidopsis, involves PRC2-based silencing of the floral repressor FLC5,6. The slow dynamics of vernalization, taking place over weeks in the cold, generate a level of stable silencing of FLC in the subsequent warm that depends quantitatively on the length of the prior cold. These features make vernalization an ideal experimental system to investigate both the maintenance of epigenetic states and the switching between them. Here, using mathematical modelling, chromatin immunoprecipitation and an FLC:GUS reporter assay, we show that the quantitative nature of vernalization is generated by H3K27me3-mediated FLC silencing in the warm in a subpopulation of cells whose number depends on the length of the prior cold. During the cold, H3K27me3 levels progressively increase at a tightly localized nucleation region within FLC. At the end of the cold, numerical simulations predict that such a nucleation region is capable of switching the bistable epigenetic state of an individual locus, with the probability of overall FLC coverage by silencing H3K27me3 marks depending on the length of cold exposure. Thus, the model predicts a bistable pattern of FLC gene expression in individual cells, a prediction we verify using the FLC:GUS reporter system. Our proposed switching mechanism, involving the local nucleation of an opposing histone modification, is likely to be widely relevant in epigenetic reprogramming.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: H3K27me3 ChIP experiments.
Figure 2: Schematic outline of mathematical model for FLC silencing.
Figure 3: Fitting model output to experimental ChIP data.
Figure 4: Validating model predictions.

References

  1. 1

    Hansen, K. H. et al. A model for transmission of the H3K27me3 epigenetic mark. Nature Cell Biol. 10, 1291–1300 (2008)

    CAS  Article  Google Scholar 

  2. 2

    Margueron, R. et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461, 762–767 (2009)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Turner, B. M. Defining an epigenetic code. Nature Cell Biol. 9, 2–6 (2007)

    CAS  Article  Google Scholar 

  4. 4

    Margueron, R. & Reinberg, D. Chromatin structure and the inheritance of epigenetic information. Nature Rev. Genet. 11, 285–296 (2010)

    CAS  Article  Google Scholar 

  5. 5

    Sheldon, C. C. et al. The FLF MADS box gene: a repressor of flowering in Arabidopsis regulated by vernalization and methylation. Plant Cell 11, 445–458 (1999)

    CAS  Article  Google Scholar 

  6. 6

    Michaels, S. D. & Amasino, R. M. FLOWERING LOCUS C encodes a novel MADS domain protein that acts as a repressor of flowering. Plant Cell 11, 949–956 (1999)

    CAS  Article  Google Scholar 

  7. 7

    Sung, S. & Amasino, R. M. Vernalization in Arabidopsis thaliana is mediated by the PHD finger protein VIN3. Nature 427, 159–164 (2004)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Greb, T. et al. The PHD finger protein VRN5 functions in the epigenetic silencing of Arabidopsis FLC . Curr. Biol. 17, 73–78 (2007)

    CAS  Article  Google Scholar 

  9. 9

    De Lucia, F., Crevillen, P., Jones, A. M., Greb, T. & Dean, C. A. PHD-Polycomb repressive complex 2 triggers the epigenetic silencing of FLC during vernalization. Proc. Natl Acad. Sci. USA 105, 16831–16836 (2008)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Wood, C. C. et al. The Arabidopsis thaliana vernalization response requires a polycomb-like protein complex that also includes VERNALIZATION INSENSITIVE 3. Proc. Natl Acad. Sci. USA 103, 14631–14636 (2006)

    ADS  Article  Google Scholar 

  11. 11

    Gendall, A. R., Levy, Y. Y., Wilson, A. & Dean, C. The VERNALIZATION 2 gene mediates the epigenetic regulation of vernalization in Arabidopsis . Cell 107, 525–535 (2001)

    CAS  Article  Google Scholar 

  12. 12

    Finnegan, E. J. & Dennis, E. S. Vernalization-induced trimethylation of histone H3 lysine 27 at FLC is not maintained in mitotically quiescent cells. Curr. Biol. 17, 1978–1983 (2007)

    CAS  Article  Google Scholar 

  13. 13

    Dodd, I. B., Micheelsen, M. A., Sneppen, K. & Thon, G. Theoretical analysis of epigenetic cell memory by nucleosome modification. Cell 129, 813–822 (2007)

    CAS  Article  Google Scholar 

  14. 14

    Salazar, J. D., Foreman, J., Carr, I. A., Rand, D. A. & Millar, A. J. Mathematical model of the epigenetic control of vernalisation in Arabidopsis thaliana . Acta Hort. (ISHS) 803, 187–192 (2008)

    Article  Google Scholar 

  15. 15

    Sedighi, M. & Sengupta, A. M. Epigenetic chromatin silencing: bistability and front propagation. Phys. Biol. 4, 246–255 (2007)

    ADS  CAS  Article  Google Scholar 

  16. 16

    David-Rus, D., Mukhopadhyay, S., Lebowitz, J. L. & Sengupta, A. M. Inheritance of epigenetic chromatin silencing. J. Theor. Biol. 258, 112–120 (2009)

    MathSciNet  CAS  Article  Google Scholar 

  17. 17

    Mukhopadhyay, S., Nagaraj, V. H. & Sengupta, A. M. Locus dependence in epigenetic chromatin silencing. Biosystems 102, 49–54 (2010)

    Article  Google Scholar 

  18. 18

    Kelemen, J. Z., Ratna, P., Scherrer, S. & Becskei, A. Spatial epigenetic control of mono- and bistable gene expression. PLoS Biol. 8, e1000332 (2010)

    Article  Google Scholar 

  19. 19

    Kaufman, P. D. & Rando, O. J. Chromatin as a potential carrier of heritable information. Curr. Opin. Cell Biol. 22, 284–290 (2010)

    CAS  Article  Google Scholar 

  20. 20

    Deal, R. B., Henikoff, J. G. & Henikoff, S. Genome-wide kinetics of nucleosome turnover determined by metabolic labeling of histones. Science 328, 1161–1164 (2010)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Reddy, G. V., Heisler, M. G., Ehrhardt, D. W. & Meyerowitz, E. M. Real-time lineage analysis reveals oriented cell divisions associated with morphogenesis at the shoot apex of Arabidopsis thaliana . Development 131, 4225–4237 (2004)

    CAS  Article  Google Scholar 

  22. 22

    Grandjean, O. et al. In vivo analysis of cell division, cell growth, and differentiation at the shoot apical meristem in Arabidopsis . Plant Cell 16, 74–87 (2004)

    CAS  Article  Google Scholar 

  23. 23

    Levy, Y. Y., Mesnage, S., Mylne, J. S., Gendall, A. R. & Dean, C. Multiple roles of Arabidopsis VRN1 in vernalization and flowering time control. Science 297, 243–246 (2002)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Bastow, R. et al. Vernalization requires epigenetic silencing of FLC by histone methylation. Nature 427, 164–167 (2004)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Sheldon, C. C. et al. Resetting of FLOWERING LOCUS C expression after epigenetic repression by vernalization. Proc. Natl Acad. Sci. USA 105, 2214–2219 (2008)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Burn, J. E., Bagnall, D. J., Metzger, J. D., Dennis, E. S. & Peacock, W. J. DNA methylation, vernalization, and the initiation of flowering. Proc. Natl Acad. Sci. USA 90, 287–291 (1993)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Swiezewski, S., Liu, F., Magusin, A. & Dean, C. Cold-induced silencing by long antisense transcripts of an Arabidopsis Polycomb target. Nature 462, 799–802 (2009)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Pierik, R. L. M. in Cellular and Molecular Aspects of Floral Induction (ed. Bernier, G.) 409–415 (Longmans, 1970)

    Google Scholar 

  29. 29

    Lee, I., Michaels, S. D., Masshardt, A. S. & Amasino, R. M. The late-flowering phenotype of FRIGIDA and mutations in LUMINIDEPENDENS is suppressed in the Landsberg erecta strain of Arabidopsis . Plant J. 6, 903–909 (1994)

    CAS  Article  Google Scholar 

  30. 30

    Zhang, X. et al. Whole-genome analysis of histone H3 lysine 27 trimethylation in Arabidopsis . PLoS Biol. 5, e129 (2007)

    Article  Google Scholar 

Download references

Acknowledgements

We thank all members of the C.D. and M.H. groups for discussions. We also thank S. Costa for suggestions to improve the FLC:GUS imagery and V. Grieneisen, S. Maree, R. Morris, S. Swiezewski and P. Wigge for comments on the manuscript. This research was supported by an Advanced Investigator European Research Council grant and the Core Strategic Grant from the Biotechnology and Biological Sciences Research Council to the John Innes Centre. M.H. also acknowledges support from The Royal Society.

Author information

Affiliations

Authors

Contributions

C.D. and M.H. conceived the study, A.A., J.S., C.D. and M.H. designed the experiments, J.S. performed the experiments, A.A. and J.S. analysed the experimental data, A.A. and M.H. designed the numerical simulations, A.A. performed the simulations and analysed the simulation data. A.A., J.S., C.D. and M.H. wrote the manuscript.

Corresponding authors

Correspondence to Caroline Dean or Martin Howard.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Text, Supplementary Figures 1-12 with legends, Supplementary Tables 1-2 and additional references. (PDF 929 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Angel, A., Song, J., Dean, C. et al. A Polycomb-based switch underlying quantitative epigenetic memory. Nature 476, 105–108 (2011). https://doi.org/10.1038/nature10241

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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