The language of covalent histone modifications

Histone proteins and the nucleosomes they form with DNA are the fundamental building blocks of eukaryotic chromatin. A diverse array of post-translational modifications that often occur on tail domains of these proteins has been well documented. Although the function of these highly conserved modifications has remained elusive, converging biochemical and genetic evidence suggests functions in several chromatin-based processes. We propose that distinct histone modifications, on one or more tails, act sequentially or in combination to form a ‘histone code’ that is, read by other proteins to bring about distinct downstream events.

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

Access options

Subscribe to this journal

Receive 51 print issues and online access

196,21 € per year

only 3,85 € per issue

Buy this article

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

Similar content being viewed by others

Multifunctional histone variants in genome function

Article 13 August 2024

Histone post-translational modifications — cause and consequence of genome function

Article 25 March 2022

Acetyl-methyllysine marks chromatin at active transcription start sites

Article 20 September 2023

References

  1. Luger,K. & Richmond,T. J. The histone tails of the nucleosome. Curr. Opin. Genet. Dev.8, 140–146 (1998). ArticleCASPubMedGoogle Scholar
  2. Kornberg,R. D. & Lorch,Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryotic chromosome. Cell98, 285–294 (1999). CASPubMedGoogle Scholar
  3. van Holde,K. E. in Chromatin (ed. Rich, A.) 111–148 (Springer, New York, 1988). Google Scholar
  4. Wolffe,A. P. & Hayes,J. J. Chromatin disruption and modification. Nucleic Acids Res.27, 711–720 (1999). ArticleCASPubMedPubMed CentralGoogle Scholar
  5. Hecht,A., Laroche,T., Strahl-Bolsinger,S., Gasser,S. M. & Grunstein,M. Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast. Cell80, 583–592 (1995). ArticleCASPubMedGoogle Scholar
  6. Edmondson,D. G., Smith,M. M. & Roth,S. Y. Repression domain of the yeast global repressor Tup1 interacts directly with histones H3 and H4. Genes Dev.10, 1247–1259 (1996). ArticleCASPubMedGoogle Scholar
  7. Luger,K., Mader,A. W., Richmond,R. K., Sargent,D. F. & Richmond,T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature389, 251–260 (1997). ArticleADSCASPubMedGoogle Scholar
  8. Hansen,J. C., Tse,C. & Wolffe,A. P. Structure and function of the core histone N-termini: more than meets the eye. Biochemistry37, 17637–17641 (1998). ArticleCASPubMedGoogle Scholar
  9. Mizzen,C. et al. Signaling to chromatin through histone modifications: how clear is the signal? Cold Spring Harb. Symp. Quant. Biol.63, 469–481 (1998). ArticleCASPubMedGoogle Scholar
  10. Turner,B. M. Decoding the nucleosome. Cell75, 5–8 (1993). ArticleCASPubMedGoogle Scholar
  11. Lopez-Rodas,G. et al. Histone deacetylase. A key enzyme for the binding of regulatory proteins to chromatin. FEBS Lett.317, 175–180 (1993). ArticleCASPubMedGoogle Scholar
  12. Loidl,P. Histone acetylation: facts and questions. Chromosoma103, 441–449 (1994). ArticleCASPubMedGoogle Scholar
  13. Tordera,V., Sendra,R. & Perez-Ortin,J. E. The role of histones and their modifications in the informative content of chromatin. Experientia49, 780–788 (1993). ArticleCASPubMedGoogle Scholar
  14. Grunstein,M. Histone acetylation in chromatin structure and transcription. Nature389, 349–352 (1997). ArticleADSCASPubMedGoogle Scholar
  15. Struhl,K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev.12, 599–606 (1998). ArticleCASPubMedGoogle Scholar
  16. Thorne,A. W., Kmiciek,D., Mitchelson,K., Sautiere,P. & Crane-Robinson,C. Patterns of histone acetylation. Eur. J. Biochem.193, 701–713 (1990). ArticleCASPubMedGoogle Scholar
  17. Kuo,M. H. et al. Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines. Nature383, 269–272 (1996). ArticleADSCASPubMedGoogle Scholar
  18. Grant,P. A. et al. Expanded lysine acetylation specificity of Gcn5 in native complexes. J. Biol. Chem.274, 5895–5900 (1999). ArticleCASPubMedGoogle Scholar
  19. Zhang,W., Bone,J. R., Edmondson,D. G., Turner,B. M. & Roth,S. Y. Essential and redundant functions of histone acetylation revealed by mutation of target lysines and loss of the Gcn5p acetyltransferase. EMBO J.17, 3155–3167 (1998). ArticleCASPubMedPubMed CentralGoogle Scholar
  20. Rojas,J. R. et al. Structure of Tetrahymena GCN5 bound to coenzyme A and a histone H3 peptide. Nature401, 93–98 (1999). ArticleADSCASPubMedGoogle Scholar
  21. Tanner,K. G. et al. Catalytic mechanism and function of invariant glutamic acid 173 from the histone acetyltransferase GCN5 transcriptional coactivator. J. Biol. Chem.274, 18157–18160 (1999). ArticleCASPubMedGoogle Scholar
  22. Trievel,R. C. et al. Crystal structure and mechanism of histone acetylation of the yeast GCN5 transcriptional coactivator. Proc. Natl Acad. Sci. USA96, 8931–8936 (1999). ArticleADSCASPubMedPubMed CentralGoogle Scholar
  23. Clements,A. et al. Crystal structure of the histone acetyltransferase domain of the human PCAF transcriptional regulator bound to coenzyme A. EMBO J.18, 3521–3532 (1999). ArticleCASPubMedPubMed CentralGoogle Scholar
  24. Lin,Y., Fletcher,C. M., Zhou,J., Allis,C. D. & Wagner,G. Solution structure of the catalytic domain of GCN5 histone acetyltransferase bound to coenzyme A. Nature400, 86–89 (1999). ArticleADSCASPubMedGoogle Scholar
  25. Sternglanz,R. & Schindelin,H. Structure and mechanism of action of the histone acetyltransferase gcn5 and similarity to other N-acetyltransferases. Proc. Natl Acad. Sci. USA96, 8807–8808 (1999). ArticleADSCASPubMedPubMed CentralGoogle Scholar
  26. Kimura,A. & Horikoshi,M. How do histone acetyltransferases select lysine residues in core histones? FEBS Lett.431, 131–133 (1998). ArticleCASPubMedGoogle Scholar
  27. Turner,B. M. & O'Neill,L. P. Histone acetylation in chromatin and chromosomes. Semin. Cell Biol.6, 229–236 (1995). ArticleCASPubMedGoogle Scholar
  28. Annunziato,A. T. in The Nucleus (ed. Wolffe, A. P.) 31–56 (JAI, Greenwich, Connecticut, 1995). BookGoogle Scholar
  29. Allis,C. D., Chicoine,L. G., Richman,R. & Schulman,I. G. Deposition-related histone acetylation in micronuclei of conjugating Tetrahymena. Proc. Natl Acad. Sci. USA82, 8048–8052 (1985). ArticleADSCASPubMedPubMed CentralGoogle Scholar
  30. Sobel,R. E., Cook,R. G., Perry,C. A., Annunziato,A. T. & Allis,C. D. Conservation of deposition-related acetylation sites in newly synthesized histones H3 and H4. Proc. Natl Acad. Sci. USA92, 1237–1241 (1995). ArticleADSCASPubMedPubMed CentralGoogle Scholar
  31. Tyler,J. K. et al. The RCAF complex mediates chromatin assembly during DNA replication and repair. Nature402, 555–560 (1999). ArticleADSCASPubMedGoogle Scholar
  32. Bradbury,E. M. Reversible histone modifications and the chromosome cell cycle. Bioessays14, 9–16 (1992). ArticleCASPubMedGoogle Scholar
  33. Koshland,D. & Strunnikov,A. Mitotic chromosome condensation. Annu. Rev. Cell Dev. Biol.12, 305–333 (1996). ArticleCASPubMedGoogle Scholar
  34. Mahadevan,L. C., Willis,A. C. & Barratt,M. J. Rapid histone H3 phosphorylation in response to growth factors, phorbol esters, okadaic acid, and protein synthesis inhibitors. Cell65, 775–783 (1991). ArticleCASPubMedGoogle Scholar
  35. Thomson,S., Mahadevan,L. C. & Clayton,A. L. MAP kinase-mediated signalling to nucleosomes and immediate-early gene induction. Semin. Cell Dev. Biol.10, 205–214 (1999). ArticleCASPubMedGoogle Scholar
  36. Chadee,D. N. et al. Increased Ser-10 phosphorylation of histone H3 in mitogen-stimulated and oncogene-transformed mouse fibroblasts. J. Biol. Chem.274, 24914–24920 (1999). ArticleCASPubMedGoogle Scholar
  37. Sassone-Corsi,P. et al. Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science285, 886–891 (1999). ArticleCASPubMedGoogle Scholar
  38. De Cesare,D., Jacquot,S., Hanauer,A. & Sassone-Corsi,P. Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene. Proc. Natl Acad. Sci. USA95, 12202–12207 (1998). ArticleADSCASPubMedPubMed CentralGoogle Scholar
  39. Thomson,S. et al. The nucleosomal response associated with immediate-early gene induction is mediated via alternative MAP kinase cascades: MSK1 as a potential histone H3/HMG-14 kinase. EMBO J.18, 4779–4793 (1999). ArticleCASPubMedPubMed CentralGoogle Scholar
  40. Jin,Y. et al. JIL-1: a novel chromosomal tandem kinase implicated in transcriptional regulation in Drosophila. Mol. Cell4, 129–135 (1999). ArticleCASPubMedGoogle Scholar
  41. Lucchesi,J. C. Dosage compensation in flies and worms: the ups and downs of X-chromosome regulation. Curr. Opin. Genet. Dev.8, 179–184 (1998). ArticleCASPubMedGoogle Scholar
  42. 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. Cell69, 375–384 (1992). ArticleCASPubMedGoogle Scholar
  43. von Holt,C. et al. Isolation and characterization of histones. Methods Enzymol.170, 431–523 (1989). ArticleCASPubMedGoogle Scholar
  44. Strahl,B. D., Ohba,R., Cook,R. G. & Allis,C. D. Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena. Proc. Natl Acad. Sci. USA96, 14967–14972 (1999). ArticleADSCASPubMedPubMed CentralGoogle Scholar
  45. Chen,D. et al. Regulation of transcription by a protein methyltransferase. Science284, 2174–2177 (1999). ArticleCASPubMedGoogle Scholar
  46. Nakajima,T. et al. The signal-dependent coactivator CBP is a nuclear target for pp90RSK. Cell86, 465–474 (1996). ArticleCASPubMedGoogle Scholar
  47. Berger,S. L. Gene activation by histone and factor acetyltransferases. Curr. Opin. Cell Biol.11, 336–341 (1999). ArticleCASPubMedGoogle Scholar
  48. Cosma,M. P., Tanaka,T. & Nasmyth,K. Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle- and developmentally regulated promoter. Cell97, 299–311 (1999). ArticleCASPubMedGoogle Scholar
  49. Krebs,J. E., Kuo,M. H., Allis,C. D. & Peterson,C. L. Cell cycle-regulated histone acetylation required for expression of the yeast HO gene. Genes Dev.13, 1412–1421 (1999). ArticleCASPubMedPubMed CentralGoogle Scholar
  50. Clark,D. et al. Chromatin structure of transcriptionally active genes. Cold Spring Harb. Symp. Quant. Biol.58, 1–6 (1993). ArticleCASPubMedGoogle Scholar
  51. Roth,S. Y. & Allis,C. D. Chromatin condensation: does histone H1 dephosphorylation play a role? Trends Biochem. Sci.17, 93–98 (1992). ArticleCASPubMedGoogle Scholar
  52. Barratt,M. J., Hazzalin,C. A., Cano,E. & Mahadevan,L. C. Mitogen-stimulated phosphorylation of histone H3 is targeted to a small hyperacetylation-sensitive fraction. Proc. Natl Acad. Sci. USA91, 4781–4785 (1994). ArticleADSCASPubMedPubMed CentralGoogle Scholar
  53. Hendzel,M. J. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma106, 348–360 (1997). ArticleCASPubMedGoogle Scholar
  54. Wei,Y., Yu,L., Bowen,J., Gorovsky,M. A. & Allis,C. D. Phosphorylation of histone H3 is required for proper chromosome condensation and segregation. Cell97, 99–109 (1999). ArticleCASPubMedGoogle Scholar
  55. Goto,H. et al. Identification of a novel phosphorylation site on histone H3 coupled with mitotic chromosome condensation. J. Biol. Chem.274, 25543–25549 (1999). ArticleCASPubMedGoogle Scholar
  56. Sullivan,K. F., Hechenberger,M. & Masri,K. Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere. J. Cell Biol.127, 581–592 (1994). ArticleCASPubMedGoogle Scholar
  57. Hirano,T. SMC-mediated chromosome mechanics: a conserved scheme from bacteria to vertebrates? Genes Dev.13, 11–19 (1999). ArticleCASPubMedGoogle Scholar
  58. De Rubertis,F. et al. The histone deacetylase RPD3 counteracts genomic silencing in Drosophila and yeast. Nature384, 589–591 (1996). ArticleADSCASPubMedGoogle Scholar
  59. Braunstein,M., Sobel,R. E., Allis,C. D., Turner,B. M. & Broach,J. R. Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. Mol. Cell. Biol.16, 4349–4356 (1996). ArticleCASPubMedPubMed CentralGoogle Scholar
  60. Dhalluin,C. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature399, 491–496 (1999). ArticleADSCASPubMedGoogle Scholar
  61. Winston,F. & Allis,C. D. The bromodomain: a chromatin-targeting module? Nature Struct. Biol.6, 601–604 (1999). ArticleCASPubMedGoogle Scholar
  62. Pawson,T. Protein modules and signalling networks. Nature373, 573–580 (1995). ArticleADSCASPubMedGoogle Scholar
  63. Roberts,S. M. & Winston,F. Essential functional interactions of SAGA, a Saccharomyces cerevisiae complex of Spt, Ada, and Gcn5 proteins, with the Snf/Swi and Srb/mediator complexes. Genetics147, 451–465 (1997). CASPubMedPubMed CentralGoogle Scholar
  64. Biggar,S. R. & Crabtree,G. R. Continuous and widespread roles for the Swi–Snf complex in transcription. EMBO J.18, 2254–2264 (1999). ArticleCASPubMedPubMed CentralGoogle Scholar
  65. Sudarsanam,P., Cao,Y., Wu,L., Laurent,B. C. & Winston,F. The nucleosome remodeling complex, Snf/Swi, is required for the maintenance of transcription in vivo and is partially redundant with the histone acetyltransferase, Gcn5. EMBO J.18, 3101–3106 (1999). ArticleCASPubMedPubMed CentralGoogle Scholar
  66. Georgel,P. T., Tsukiyama,T. & Wu,C. Role of histone tails in nucleosome remodeling by Drosophila NURF. EMBO J.16, 4717–4726 (1997). ArticleCASPubMedPubMed CentralGoogle Scholar
  67. Luduena,R. F. Multiple forms of tubulin: different gene products and covalent modifications. Int. Rev. Cytol.178, 207–275 (1998). ArticleCASPubMedGoogle Scholar
  68. Luduena,R. F., Banerjee,A. & Khan,I. A. Tubulin structure and biochemistry. Curr. Opin. Cell Biol.4, 53–57 (1992). ArticleCASPubMedGoogle Scholar
  69. Nogales,E., Whittaker,M., Milligan,R. A. & Downing,K. H. High-resolution model of the microtubule. Cell96, 79–88 (1999). ArticleCASPubMedGoogle Scholar

Acknowledgements

Research surrounding this topic in our laboratory is supported by grants from the NIH to C.D.A. and B.D.S. We wish to thank current laboratory members, especially C. A. Mizzen, for critical review of this manuscript, and T. K. Archer and C. L. Smith for kindly sharing unpublished data.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Virginia Health Science Center, Charlottesville, 22908, Virginia, USA Brian D. Strahl & C. David Allis
  1. Brian D. Strahl