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.

  • Review Article
  • Published:

How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers

Nature Structural & Molecular Biology volume 14, pages 1025–1040 (2007)Cite this article

Abstract

Histones comprise the major protein component of chromatin, the scaffold in which the eukaryotic genome is packaged, and are subject to many types of post-translational modifications (PTMs), especially on their flexible tails. These modifications may constitute a 'histone code' and could be used to manage epigenetic information that helps extend the genetic message beyond DNA sequences. This proposed code, read in part by histone PTM–binding 'effector' modules and their associated complexes, is predicted to define unique functional states of chromatin and/or regulate various chromatin-templated processes. A wealth of structural and functional data show how chromatin effector modules target their cognate covalent histone modifications. Here we summarize key features in molecular recognition of histone PTMs by a diverse family of 'reader pockets', highlighting specific readout mechanisms for individual marks, common themes and insights into the downstream functional consequences of the interactions. Changes in these interactions may have far-reaching implications for human biology and disease, notably cancer.

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: Histone post-translational modifications and their binding partners.
Figure 2: Readout of acetyllysine marks by bromodomains.
Figure 3: Readout of methyllysine marks by Royal-superfamily modules.
Figure 4: Readout of modified and unmodified histone lysine marks by PHD finger modules.
Figure 5: Readout of an unmodified arginine by the WD40 repeat of WDR5.
Figure 6: Readout of phosphoserine marks by 14-3-3 and BRCT domains.
Figure 7: Combinations of PTM-binding sites generate different specifities.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Allis, C.D., Jenuwein, T., Reinberg, D. & Caparros, M.L (eds.). Epigenetics (Cold Spring Harbor Laboratory Press, Woodbury, New York, 2006).

    Google Scholar 

  2. Berger, S.L. The complex language of chromatin regulation during transcription. Nature 447, 407–412 (2007).

    CAS  PubMed  Google Scholar 

  3. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Pokholok, D.K. et al. Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122, 517–527 (2005).

    CAS  PubMed  Google Scholar 

  5. Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Mikkelsen, T.S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).

    CAS  PubMed  Google Scholar 

  8. Strahl, B.D. & Allis, C.D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Ura, K., Kurumizaka, H., Dimitrov, S., Almouzni, G. & Wolffe, A.P. Histone acetylation: influence on transcription, nucleosome mobility and positioning, and linker histone-dependent transcriptional repression. EMBO J. 16, 2096–2107 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shogren-Knaak, M. et al. Histone H4–K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Ahn, S.H. et al. Sterile 20 kinase phosphorylates histone H2B at serine 10 during hydrogen peroxide-induced apoptosis in S. cerevisiae. Cell 120, 25–36 (2005).

    CAS  PubMed  Google Scholar 

  12. Cosgrove, M.S., Boeke, J.D. & Wolberger, C. Regulated nucleosome mobility and the histone code. Nat. Struct. Mol. Biol. 11, 1037–1043 (2004).

    CAS  PubMed  Google Scholar 

  13. Wolffe, A.P. & Hayes, J.J. Chromatin disruption and modification. Nucleic Acids Res. 27, 711–720 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Seet, B.T., Dikic, I., Zhou, M.M. & Pawson, T. Reading protein modifications with interaction domains. Nat. Rev. Mol. Cell Biol. 7, 473–483 (2006).

    CAS  PubMed  Google Scholar 

  15. Ruthenburg, A.J., Allis, C.D. & Wysocka, J. Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol. Cell 25, 15–30 (2007).

    CAS  PubMed  Google Scholar 

  16. Cheung, P., Allis, C.D. & Sassone-Corsi, P. Signaling to chromatin through histone modifications. Cell 103, 263–271 (2000).

    CAS  PubMed  Google Scholar 

  17. Allfrey, V.G., Faulkner, R. & Mirsky, A.E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl. Acad. Sci. USA 51, 786–794 (1964).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Taunton, J., Hassig, C.A. & Schreiber, S.L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408–411 (1996).

    CAS  PubMed  Google Scholar 

  19. Brownell, J.E. et al. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84, 843–851 (1996).

    CAS  PubMed  Google Scholar 

  20. Dhalluin, C. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491–496 (1999).

    CAS  PubMed  Google Scholar 

  21. Zeng, L. & Zhou, M.M. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 513, 124–128 (2002).

    CAS  PubMed  Google Scholar 

  22. Owen, D.J. et al. The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p. EMBO J. 19, 6141–6149 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Kuo, M.H. et al. Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines. Nature 383, 269–272 (1996).

    CAS  PubMed  Google Scholar 

  24. Jacobson, R.H., Ladurner, A.G., King, D.S. & Tjian, R. Structure and function of a human TAFII250 double bromodomain module. Science 288, 1422–1425 (2000).

    CAS  PubMed  Google Scholar 

  25. VanDemark, A.P. et al. Autoregulation of the rsc4 tandem bromodomain by gcn5 acetylation. Mol. Cell 27, 817–828 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kasten, M. et al. Tandem bromodomains in the chromatin remodeler RSC recognize acetylated histone H3 Lys14. EMBO J. 23, 1348–1359 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Cheng, X., Collins, R.E. & Zhang, X. Structural and sequence motifs of protein (histone) methylation enzymes. Annu. Rev. Biophys. Biomol. Struct. 34, 267–294 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Shi, Y. & Whetstine, J.R. Dynamic regulation of histone lysine methylation by demethylases. Mol. Cell 25, 1–14 (2007).

    CAS  PubMed  Google Scholar 

  29. Swigut, T. & Wysocka, J. H3K27 demethylase at last: what it means for memory and plasticity of gene expression in developmental processes. Cell 131, 29–32 (2007).

    CAS  PubMed  Google Scholar 

  30. Martin, C. & Zhang, Y. The diverse functions of histone lysine methylation. Nat. Rev. Mol. Cell Biol. 6, 838–849 (2005).

    CAS  PubMed  Google Scholar 

  31. Guenther, M.G., Levine, S.S., Boyer, L.A., Jaenisch, R. & Yuung, R.A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–78 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bernstein, B.E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    CAS  PubMed  Google Scholar 

  33. Hughes, R.M., Wiggins, K.R., Khorasanizadeh, S. & Waters, M.L. Recognition of trimethyllysine by a chromodomain is not driven by the hydrophobic effect. Proc. Natl. Acad. Sci. USA 104, 11184–11188 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ma, J.C. & Dougherty, D.A. Cation-π Interaction. Chem. Rev. 97, 1303–1324 (1997).

    CAS  PubMed  Google Scholar 

  35. Li, H. et al. Structural basis for lower lysine methylation state-specific readout by MBT repeats and an engineered PHD finger. Mol. Cell (in the press).

  36. Botuyan, M.V. et al. Structural basis for the methylation state-specific recognition of histone H4–K20 by 53BP1 and Crb2 in DNA repair. Cell 127, 1361–1373 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Burley, S.K. & Petsko, G.A. Weakly polar interactions in proteins. Adv. Protein Chem. 39, 125–189 (1988).

    CAS  PubMed  Google Scholar 

  38. Maurer-Stroh, S. et al. The Tudor domain 'Royal Family': Tudor, plant Agenet, Chromo, PWWP and MBT domains. Trends Biochem. Sci. 28, 69–74 (2003).

    CAS  PubMed  Google Scholar 

  39. Pena, P.V. et al. Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 442, 100–103 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Li, H. et al. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442, 91–95 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Paro, R. & Hogness, D.S. The Polycomb protein shares a homologous domain with a heterochromatin-associated protein of Drosophila. Proc. Natl. Acad. Sci. USA 88, 263–267 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    CAS  PubMed  Google Scholar 

  43. Bannister, A.J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).

    CAS  PubMed  Google Scholar 

  44. Jacobs, S.A. et al. Specificity of the HP1 chromo domain for the methylated N-terminus of histone H3. EMBO J. 20, 5232–5241 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Jacobs, S.A. & Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295, 2080–2083 (2002).

    CAS  PubMed  Google Scholar 

  46. Nielsen, P.R. et al. Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature 416, 103–107 (2002).

    CAS  PubMed  Google Scholar 

  47. Fischle, W. et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev. 17, 1870–1881 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Min, J., Zhang, Y. & Xu, R.M. Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev. 17, 1823–1828 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Nielsen, A.L. et al. Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins. Mol. Cell 7, 729–739 (2001).

    CAS  PubMed  Google Scholar 

  50. Zhao, T., Heyduk, T., Allis, C.D. & Eissenberg, J.C. Heterochromatin protein 1 binds to nucleosomes and DNA in vitro. J. Biol. Chem. 275, 28332–28338 (2000).

    CAS  PubMed  Google Scholar 

  51. Lusser, A., Urwin, D.L. & Kadonaga, J.T. Distinct activities of CHD1 and ACF in ATP-dependent chromatin assembly. Nat. Struct. Mol. Biol. 12, 160–166 (2005).

    CAS  PubMed  Google Scholar 

  52. Sims, R.J. III, Belotserkovskaya, R. & Reinberg, D. Elongation by RNA polymerase II: the short and long of it. Genes Dev. 18, 2437–2468 (2004).

    CAS  PubMed  Google Scholar 

  53. Konev, A.Y. et al. CHD1 motor protein is required for deposition of histone variant H3.3 into chromatin in vivo. Science 317, 1087–1090 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Taverna, S.D. et al. Long-distance combinatorial linkage between methylation and acetylation on histone H3 N termini. Proc. Natl. Acad. Sci. USA 104, 2086–2091 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Hake, S.B. et al. Expression patterns and post-translational modifications associated with mammalian histone H3 variants. J. Biol. Chem. 281, 559–568 (2006).

    CAS  PubMed  Google Scholar 

  56. Pray-Grant, M.G., Daniel, J.A., Schieltz, D., Yates, J.R. III & Grant, P.A. Chd1 chromodomain links histone H3 methylation with SAGA- and SLIK-dependent acetylation. Nature 433, 434–438 (2005).

    CAS  PubMed  Google Scholar 

  57. Flanagan, J.F. et al. Double chromodomains cooperate to recognize the methylated histone H3 tail. Nature 438, 1181–1185 (2005).

    CAS  PubMed  Google Scholar 

  58. Sims, R.J. III et al. Human but not yeast CHD1 binds directly and selectively to histone H3 methylated at lysine 4 via its tandem chromodomains. J. Biol. Chem. 280, 41789–41792 (2005).

    CAS  PubMed  Google Scholar 

  59. Okuda, M., Horikoshi, M. & Nishimura, Y. Structural polymorphism of chromodomains in Chd1. J. Mol. Biol. 365, 1047–1062 (2007).

    CAS  PubMed  Google Scholar 

  60. Klose, R.J. et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442, 312–316 (2006).

    CAS  PubMed  Google Scholar 

  61. Whetstine, J.R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).

    CAS  PubMed  Google Scholar 

  62. Klose, R.J., Kallin, E.M. & Zhang, Y. JmjC-domain-containing proteins and histone demethylation. Nat. Rev. Genet. 7, 715–727 (2006).

    CAS  PubMed  Google Scholar 

  63. Huang, Y., Fang, J., Bedford, M.T., Zhang, Y. & Xu, R.M. Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A. Science 312, 748–751 (2006).

    CAS  PubMed  Google Scholar 

  64. Kim, J. et al. Tudor, MBT and chromo domains gauge the degree of lysine methylation. EMBO Rep. 7, 397–403 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Sanders, S.L. et al. Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell 119, 603–614 (2004).

    CAS  PubMed  Google Scholar 

  66. Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406–411 (2004).

    CAS  PubMed  Google Scholar 

  67. Huang, J. et al. p53 is regulated by the lysine demethylase LSD1. Nature 449, 105–108 (2007).

    CAS  PubMed  Google Scholar 

  68. Koga, H. et al. A human homolog of Drosophila lethal(3)malignant brain tumor (l(3)mbt) protein associates with condensed mitotic chromosomes. Oncogene 18, 3799–3809 (1999).

    CAS  PubMed  Google Scholar 

  69. Pirrotta, V. Chromatin-silencing mechanisms in Drosophila maintain patterns of gene expression. Trends Genet. 13, 314–318 (1997).

    CAS  PubMed  Google Scholar 

  70. Boccuni, P., MacGrogan, D., Scandura, J.M. & Nimer, S.D. The human L(3)MBT polycomb group protein is a transcriptional repressor and interacts physically and functionally with TEL (ETV6). J. Biol. Chem. 278, 15412–15420 (2003).

    CAS  PubMed  Google Scholar 

  71. Trojer, P. et al. L3MBTL1, a histone-methylation-dependent chromatin lock. Cell 129, 915–928 (2007).

    CAS  PubMed  Google Scholar 

  72. Wang, W.K. et al. Malignant brain tumor repeats: a three-leaved propeller architecture with ligand/peptide binding pockets. Structure 11, 775–789 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002).

    CAS  PubMed  Google Scholar 

  74. Taverna, S.D. et al. Yng1 PHD finger binding to H3 trimethylated at K4 promotes NuA3 HAT activity at K14 of H3 and transcription at a subset of targeted ORFs. Mol. Cell 24, 785–796 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Vermeulen, M. et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131, 58–69 (2007).

    CAS  PubMed  Google Scholar 

  76. Tsukiyama, T. & Wu, C. Purification and properties of an ATP-dependent nucleosome remodeling factor. Cell 83, 1011–1020 (1995).

    CAS  PubMed  Google Scholar 

  77. Mizuguchi, G., Tsukiyama, T., Wisniewski, J. & Wu, C. Role of nucleosome remodeling factor NURF in transcriptional activation of chromatin. Mol. Cell 1, 141–150 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  79. Bienz, M. The PHD finger, a nuclear protein-interaction domain. Trends Biochem. Sci. 31, 35–40 (2006).

    CAS  PubMed  Google Scholar 

  80. Doyon, Y. et al. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol. Cell 21, 51–64 (2006).

    CAS  PubMed  Google Scholar 

  81. Millar, C.B. & Grunstein, M. Genome-wide patterns of histone modifications in yeast. Nat. Rev. Mol. Cell Biol. 7, 657–666 (2006).

    CAS  PubMed  Google Scholar 

  82. Martin, D.G. et al. The Yng1p PHD finger is a methyl-histone binding module that recognizes lysine 4 methylated histone H3. Mol. Cell. Biol. 26, 7871–7879 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Shi, X. et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Ruthenburg, A.J., Li, H., Taverna, S.D., Patel, D.J. & Allis, C.D. Multivalent readout of histone modifications by linked effector modules on a nucleosome scaffold. Nat. Rev. Mol. Cell Biol. (in the press).

  85. 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).

    CAS  PubMed  Google Scholar 

  86. Ooi, S.K. et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448, 714–717 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lan, F. et al. Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression. Nature 448, 718–722 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Couture, J.F., Collazo, E. & Trievel, R.C. Molecular recognition of histone H3 by the WD40 protein WDR5. Nat. Struct. Mol. Biol. 13, 698–703 (2006).

    CAS  PubMed  Google Scholar 

  89. Ruthenburg, A.J. et al. Histone H3 recognition and presentation by the WDR5 module of the MLL1 complex. Nat. Struct. Mol. Biol. 13, 704–712 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Schuetz, A. et al. Structural basis for molecular recognition and presentation of histone H3 by WDR5. EMBO J. 25, 4245–4252 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Han, Z. et al. Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. Mol. Cell 22, 137–144 (2006).

    CAS  PubMed  Google Scholar 

  92. Hakimi, M.A. et al. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl. Acad. Sci. USA 99, 7420–7425 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    CAS  PubMed  Google Scholar 

  94. Marmorstein, L.Y. et al. A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression. Cell 104, 247–257 (2001).

    CAS  PubMed  Google Scholar 

  95. Gruenbaum, Y., Cedar, H. & Razin, A. Substrate and sequence specificity of a eukaryotic DNA methylase. Nature 295, 620–622 (1982).

    CAS  PubMed  Google Scholar 

  96. Bestor, T.H. & Ingram, V.M. Two DNA methyltransferases from murine erythroleukemia cells: purification, sequence specificity, and mode of interaction with DNA. Proc. Natl. Acad. Sci. USA 80, 5559–5563 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Okano, M., Xie, S. & Li, E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat. Genet. 19, 219–220 (1998).

    CAS  PubMed  Google Scholar 

  98. Bourc'his, D., Xu, G.L., Lin, C.S., Bollman, B. & Bestor, T.H. Dnmt3L and the establishment of maternal genomic imprints. Science 294, 2536–2539 (2001).

    CAS  PubMed  Google Scholar 

  99. Argentaro, A. et al. Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX. Proc. Natl. Acad. Sci. USA 104, 11939–11944 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Yokoyama, A. et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol. Cell. Biol. 24, 5639–5649 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Wysocka, J. et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 121, 859–872 (2005).

    CAS  PubMed  Google Scholar 

  102. Dou, Y. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat. Struct. Mol. Biol. 13, 713–719 (2006).

    CAS  PubMed  Google Scholar 

  103. Verreault, A., Kaufman, P.D., Kobayashi, R. & Stillman, B. Nucleosomal DNA regulates the core-histone-binding subunit of the human Hat1 acetyltransferase. Curr. Biol. 8, 96–108 (1998).

    CAS  PubMed  Google Scholar 

  104. Muslin, A.J., Tanner, J.W., Allen, P.M. & Shaw, A.S. Interaction of 14–3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell 84, 889–897 (1996).

    CAS  PubMed  Google Scholar 

  105. Yaffe, M.B. et al. The structural basis for 14–3-3:phosphopeptide binding specificity. Cell 91, 961–971 (1997).

    CAS  PubMed  Google Scholar 

  106. Dougherty, M.K. & Morrison, D.K. Unlocking the code of 14–3-3. J. Cell Sci. 117, 1875–1884 (2004).

    CAS  PubMed  Google Scholar 

  107. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Soloaga, A. et al. MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. EMBO J. 22, 2788–2797 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Nowak, S.J. & Corces, V.G. Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation. Trends Genet. 20, 214–220 (2004).

    CAS  PubMed  Google Scholar 

  110. Duncan, E.A., Anest, V., Cogswell, P. & Baldwin, A.S. The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylation. J. Biol. Chem. 281, 12521–12525 (2006).

    CAS  PubMed  Google Scholar 

  111. Cheung, P. et al. Synergistic coupling of histone H3 phosphorylation and acetylation in response to epidermal growth factor stimulation. Mol. Cell 5, 905–915 (2000).

    CAS  PubMed  Google Scholar 

  112. Macdonald, N. et al. Molecular basis for the recognition of phosphorylated and phosphoacetylated histone h3 by 14–3-3. Mol. Cell 20, 199–211 (2005).

    CAS  PubMed  Google Scholar 

  113. Downs, J.A., Nussenzweig, M.C. & Nussenzweig, A. Chromatin dynamics and the preservation of genetic information. Nature 447, 951–958 (2007).

    CAS  PubMed  Google Scholar 

  114. Rogakou, E.P., Pilch, D.R., Orr, A.H., Ivanova, V.S. & Bonner, W.M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).

    CAS  PubMed  Google Scholar 

  115. Burma, S., Chen, B.P., Murphy, M., Kurimasa, A. & Chen, D.J. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J. Biol. Chem. 276, 42462–42467 (2001).

    CAS  PubMed  Google Scholar 

  116. Peng, A. & Chen, P.L. NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. J. Biol. Chem. 278, 8873–8876 (2003).

    CAS  PubMed  Google Scholar 

  117. Lee, M.S., Edwards, R.A., Thede, G.L. & Glover, J.N. Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the gamma-H2AX histone tail. J. Biol. Chem. 280, 32053–32056 (2005).

    CAS  PubMed  Google Scholar 

  118. Stucki, M. et al. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123, 1213–1226 (2005).

    CAS  PubMed  Google Scholar 

  119. Clapperton, J.A. et al. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat. Struct. Mol. Biol. 11, 512–518 (2004).

    CAS  PubMed  Google Scholar 

  120. Wu, G. et al. Structure of a β-TrCP1-Skp1-β-catenin complex: destruction motif binding and lysine specificity of the SCF(β-TrCP1) ubiquitin ligase. Mol. Cell 11, 1445–1456 (2003).

    CAS  PubMed  Google Scholar 

  121. Xiong, J.P. et al. Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science 294, 339–345 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Wall, M.A. et al. The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2. Cell 83, 1047–1058 (1995).

    CAS  PubMed  Google Scholar 

  123. Hirota, T., Lipp, J.J., Toh, B.H. & Peters, J.M. Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature 438, 1176–1180 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  125. Fischle, W., Wang, Y. & Allis, C.D. Binary switches and modification cassettes in histone biology and beyond. Nature 425, 475–479 (2003).

    CAS  PubMed  Google Scholar 

  126. Sampath, S.C. et al. Methylation of histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol. Cell 27, 596–608 (2007).

    CAS  PubMed  Google Scholar 

  127. Wang, G.G., Allis, C.D. & Chi, P. Chromatin remodeling and cancer, part I: covalent histone modifications. Trends Mol. Med. 13, 363–372 (2007).

    CAS  PubMed  Google Scholar 

  128. Hsu, J.Y. et al. Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell 102, 279–291 (2000).

    CAS  PubMed  Google Scholar 

  129. Chen, C.C., Smith, D.L., Bruegger, B.B., Halpern, R.M. & Smith, R.A. Occurrence and distribution of acid-labile histone phosphates in regenerating rat liver. Biochemistry 13, 3785–3789 (1974).

    CAS  PubMed  Google Scholar 

  130. Carrozza, M.J. et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123, 581–592 (2005).

    CAS  PubMed  Google Scholar 

  131. Joshi, A.A. & Struhl, K. Eaf3 chromodomain interaction with methylated H3–K36 links histone deacetylation to Pol II elongation. Mol. Cell 20, 971–978 (2005).

    CAS  PubMed  Google Scholar 

  132. Li, B. et al. Combined action of PHD and chromo domains directs the Rpd3S HDAC to transcribed chromatin. Science 316, 1050–1054 (2007).

    CAS  PubMed  Google Scholar 

  133. Allis, C.D., Bowen, J.K., Abraham, G.N., Glover, C.V. & Gorovsky, M.A. Proteolytic processing of histone H3 in chromatin: a physiologically regulated event in Tetrahymena micronuclei. Cell 20, 55–64 (1980).

    CAS  PubMed  Google Scholar 

  134. Garcia, B.A., Pesavento, J.J., Mizzen, C.A. & Kelleher, N.L. Pervasive combinatorial modification of histone H3 in human cells. Nat. Methods 4, 487–489 (2007).

    CAS  PubMed  Google Scholar 

  135. Strahl, B.D. et al. Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1. Curr. Biol. 11, 996–1000 (2001).

    CAS  PubMed  Google Scholar 

  136. Wang, H. et al. Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 293, 853–857 (2001).

    CAS  PubMed  Google Scholar 

  137. An, W., Kim, J. & Roeder, R.G. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 117, 735–748 (2004).

    CAS  PubMed  Google Scholar 

  138. Cuthbert, G.L. et al. Histone deimination antagonizes arginine methylation. Cell 118, 545–553 (2004).

    CAS  PubMed  Google Scholar 

  139. Wang, Y. et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306, 279–283 (2004).

    CAS  PubMed  Google Scholar 

  140. Selenko, P. et al. SMN tudor domain structure and its interaction with the Sm proteins. Nat. Struct. Biol. 8, 27–31 (2001).

    CAS  PubMed  Google Scholar 

  141. Sprangers, R., Groves, M.R., Sinning, I. & Sattler, M. High-resolution X-ray and NMR structures of the SMN Tudor domain: conformational variation in the binding site for symmetrically dimethylated arginine residues. J. Mol. Biol. 327, 507–520 (2003).

    CAS  PubMed  Google Scholar 

  142. Kirmizis, A. et al. Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation. Nature 449, 928–932 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Guccione, E. et al. Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 449; 933–937 (2007)

    CAS  PubMed  Google Scholar 

  144. Ahn, S.H., Diaz, R.L., Grunstein, M. & Allis, C.D. Histone H2B deacetylation at lysine 11 is required for yeast apoptosis induced by phosphorylation of H2B at serine 10. Mol. Cell 24, 211–220 (2006).

    CAS  PubMed  Google Scholar 

  145. Latham, J.A. & Dent, S.Y.R. Cross-regulation of histone modifications. Nat. Struct. Mol. Biol. 14, 1017–1024 (2007).

    CAS  PubMed  Google Scholar 

  146. Feinberg, A.P. Phenotypic plasticity and the epigenetics of human disease. Nature 447, 433–440 (2007).

    CAS  PubMed  Google Scholar 

  147. Spadaccini, R., Perrin, H., Bottomley, M.J., Ansieau, S. & Sattler, M. Structure and functional analysis of the MYND domain. J. Mol. Biol. 358, 498–508 (2006).

    CAS  PubMed  Google Scholar 

  148. Liu, Y. et al. Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO's activity. Cancer Cell 11, 483–497 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Chang, B., Chen, Y., Zhao, Y. & Bruick, R.K. JMJD6 is a histone arginine demethylase. Science 318, 444–447 (2007).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to all of the researchers whose important contributions could not be acknowledged because of space constraints. We thank members of the Patel and Allis laboratories as well as the anonymous reviewers for critically reading the manuscript, and A. VanDemark (University of Pittsburgh) and C.P. Hill (University of Utah) for providing coordinates for Rsc4p in Figure 2e. D.J.P. is supported by funds from the Abby Rockefeller Mauze Trust and the Dewitt Wallace and Maloris Foundations, C.D.A. and S.D.T are supported by US National Institutes of Health grants GM53512 and GM63959 and by funds from The Rockefeller University, and A.J.R. is supported by a postdoctoral fellowship from the Irvington Foundation.

Author information

Author notes

  1. Sean D Taverna and Haitao Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Chromatin Biology, The Rockefeller University, New York, 10021, New York, USA

    Sean D Taverna, Alexander J Ruthenburg & C David Allis

  2. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Haitao Li & Dinshaw J Patel

Authors
  1. Sean D Taverna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haitao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander J Ruthenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C David Allis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dinshaw J Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sean D Taverna, Haitao Li or Dinshaw J Patel.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taverna, S., Li, H., Ruthenburg, A. et al. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14, 1025–1040 (2007). https://doi.org/10.1038/nsmb1338

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb1338

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