Defining an epigenetic code

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The nucleosome surface is decorated with an array of enzyme-catalysed modifications on histone tails. These modifications have well-defined roles in a variety of ongoing chromatin functions, often by acting as receptors for non-histone proteins, but their longer-term effects are less clear. Here, an attempt is made to define how histone modifications operate as part of a predictive and heritable epigenetic code that specifies patterns of gene expression through differentiation and development.

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Figure 1: Histone modifications can generate both short-term and long-term outcomes.
Figure 2: A hypothetical illustration of how an epigenetic code may work in the pre-implantation embryo.


  1. 1

    Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389, 251–260 (1997).

  2. 2

    Margueron, R., Trojer, P. & Reinberg, D. The key to development: interpreting the histone code? Curr. Opin. Genet. Dev. 15, 163–176 (2005).

  3. 3

    Nightingale, K. P., O'Neill, L. P. & Turner, B. M. Histone modifications: signalling receptors and potential elements of a heritable epigenetic code. Curr. Opin. Genet. Dev. 16, 125–136 (2006).

  4. 4

    Turner, B. M., Birley, A. J. & Lavender, J. Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei. Cell 69, 375–384 (1992).

  5. 5

    Hazzalin, C. A. & Mahadevan, L. C. Dynamic acetylation of all lysine 4-methylated histone H3 in the mouse nucleus: analysis at c-fos and c-jun. PLoS Biol. 3, e393 (2005).

  6. 6

    Metivier, R. et al. Estrogen receptor-α directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115, 751–763 (2003).

  7. 7

    Schreiber, S. L. & Bernstein, B. E. Signaling network model of chromatin. Cell 111, 771–778 (2002).

  8. 8

    Fischle, W. et al. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438, 1116–1122 (2005).

  9. 9

    Mateescu, B., England, P., Halgand, F., Yaniv, M. & Muchardt, C. Tethering of HP1 proteins to chromatin is relieved by phosphoacetylation of histone H3. EMBO Rep. 5, 490–496 (2004).

  10. 10

    Hake, S. B. & Allis, C. D. Histone H3 variants and their potential role in indexing mammalian genomes: the “H3 barcode hypothesis”. Proc. Natl Acad. Sci. USA 103, 6428–6435 (2006).

  11. 11

    Peters, A. H. et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol. Cell 12, 1577–1589 (2003).

  12. 12

    Heard, E. Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome. Curr. Opin. Genet. Dev. 15, 482–489 (2005).

  13. 13

    Barbieri, M. The Organic Codes; An Introduction to Semantic Biology (Cambridge University Press, Cambridge, 2003).

  14. 14

    Segal, E. et al. A genomic code for nucleosome positioning. Nature 442, 772–778 (2006).

  15. 15

    Crick, F. H. On the genetic code. Science 139, 461–464 (1963).

  16. 16

    Crick, F. H. The recent excitement in the coding problem. Progress in Nucleic Acid Research 1, 163–217 (1963).

  17. 17

    Dion, M. F., Altschuler, S. J., Wu, L. F. & Rando, O. J. Genomic characterization reveals a simple histone H4 acetylation code. Proc. Natl Acad. Sci. USA 102, 5501–5506 (2005).

  18. 18

    Liu, C. L. et al. Single-nucleosome mapping of histone modifications in S. cerevisiae. PLoS Biol. 3, e328 (2005).

  19. 19

    Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).

  20. 20

    Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet 33, 245–254 (2003).

  21. 21

    Sun, Z. W. & Allis, C. D. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature 418, 104–108 (2002).

  22. 22

    Wilson, C. B. & Merkenschlager, M. Chromatin structure and gene regulation in T cell development and function. Curr. Opin. Immunol. 18, 143–151 (2006).

  23. 23

    Gilbert, N., Gilchrist, S. & Bickmore, W. A. Chromatin organization in the mammalian nucleus. Int. Rev. Cytol. 242, 283–336 (2005).

  24. 24

    Sproul, D., Gilbert, N. & Bickmore, W. A. The role of chromatin structure in regulating the expression of clustered genes. Nature Rev. Genet. 6, 775–781 (2005).

  25. 25

    Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).

  26. 26

    Ralston, A. & Rossant, J. Genetic regulation of stem cell origins in the mouse embryo. Clin. Genet. 68, 106–112 (2005).

  27. 27

    Szutorisz, H. et al. Formation of an active tissue-specific chromatin domain initiated by epigenetic marking at the embryonic stem cell stage. Mol. Cell Biol. 25, 1804–1820 (2005).

  28. 28

    Szutorisz, H. & Dillon, N. The epigenetic basis for embryonic stem cell pluripotency. Bioessays 27, 1286–1293 (2005).

  29. 29

    Chambeyron, S. & Bickmore, W. A. Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. Genes Dev. 18, 1119–1130 (2004).

  30. 30

    Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006).

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I am grateful to M. Barbieri for drawing my attention to the world of semiotics, and to A. Ferguson-Smith and colleagues in the Chromatin and Gene Expression Group for their thoughts, criticisms and insights.

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