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:

Histone acetyltransferase complexes: one size doesn't fit all

Nature Reviews Molecular Cell Biology volume 8, pages 284–295 (2007)Cite this article

Key Points

  • Histone acetyltransferase (HAT) enzymes are a diverse group of proteins that are evolutionarily conserved from yeast to humans.

  • Although originally identified as enzymes that acetylate histones, a growing number of non-histone substrates have been identified for HATs, which implies a more general role in regulating the function of an ever-growing number of proteins.

  • Based on structural evidence, HAT enzymes can accommodate a number of substrates; therefore, the functions of these enzymes are much more varied than simply modifying histones post-translationally.

  • Although the HAT enzyme is the catalytic subunit that is required for activity, it is the context in which these enzymes exist that provides the enzyme with specificity. Most HAT enzymes exist in multiprotein complexes, and it is these proteins that allow the enzymes to carry out specific functions in the cell.

  • Many HAT-associated proteins contain domains, which can recognize and bind modified protein residues. This includes bromo-, chromo- and PHD (plant homeodomain) domains, which are able to bind modified histones.

  • HAT enzymes carry out several functions in the cell, ranging from repairing regions of DNA damage to maintaining overall genomic integrity.

  • Future work needs to focus on understanding developmental and tissue-specific HAT complexes while continuing to explore the mechanisms by which an organism maintains the balance of acetylation.

Abstract

Over the past 10 years, the study of histone acetyltransferases (HATs) has advanced significantly, and a number of HATs have been isolated from various organisms. It emerged that HATs are highly diverse and generally contain multiple subunits. The functions of the catalytic subunit depend largely on the context of the other subunits in the complex. We are just beginning to understand the specialized roles of HAT complexes in chromosome decondensation, DNA-damage repair and the modification of non-histone substrates, as well as their role in the broader epigenetic landscape, including the role of protein domains within HAT complexes and the dynamic interplay between HAT complexes and existing histone modifications.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Consequences of histone H4 lysine 16 acetylation.
Figure 2: Histone acetyltransferases and DNA repair.
Figure 3: Structural basis for histone acetyltransferase substrate recognition.

Similar content being viewed by others

References

  1. Waddington, C. H. The epigenotype. Endeavor 1, 18–20 (1942).

    Google Scholar 

  2. Waddington, C. H. Principles of Embryology (Macmillan, New York, 1956).

    Google Scholar 

  3. Kornberg, R. D. & Lorch, Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98, 285–294 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Goll, M. G. & Bestor, T. H. Histone modification and replacement in chromatin activation. Genes Dev. 16, 1739–1742 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Grant, P. A. A tale of histone modifications. Genome Biol. 2, REVIEWS0003 (2001).

  6. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Brownell, J. E. & Allis, C. D. Special HATs for special occasions: linking histone acetylation to chromatin assembly and gene activation. Curr. Opin. Genes Dev. 6, 176–184 (1996).

    Article  CAS  Google Scholar 

  8. Cano, A. & Pestana, A. Purification and properties of a histone acetyltransferase from Artemia salina, highly efficient with H1 histone. Eur. J. Biochem. 97, 65–72 (1979).

    Article  CAS  PubMed  Google Scholar 

  9. Kleff, S., Andrulis, E. D., Anderson, C. W. & Sternglanz, R. Identification of a gene encoding a yeast histone H4 acetyltransferase. J. Biol. Chem. 270, 24674–24677 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. Grant, P. A. et al. Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. Genes Dev. 11, 1640–1650 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Carrozza, M. J., Utley, R. T., Workman, J. L. & Coté, J. The diverse functions of histone acetyltransferase complexes. Trends Genet. 19, 321–329 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Kimura, A., Matsubara, K. & Horikoshi, M. A decade of histone acetylation: marking eukaryotic chromosomes with specific codes. J. Biochem. (Tokyo) 138, 647–662 (2005).

    Article  CAS  Google Scholar 

  14. Utley, R. T. & Côté, J. The MYST family of histone acetyltransferases. Curr. Top. Microbiol. Immunol. 274, 203–236 (2002).

    Google Scholar 

  15. Yang, X. J. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 32, 959–976 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ekwall, K. Genome-wide analysis of HDAC function. Trends Genet. 21, 608–615 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Workman, J. L. Nucleosome displacement in transcription. Genes Dev. 20, 2009–2017 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Doi, M., Hirayama, J. & Sassone-Corsi, P. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125, 497–508 (2006). Describes the identification of the circadian rhythm master regulator, CLOCK, as a HAT that functions with BMAL1 to carry out its activity.

    Article  CAS  PubMed  Google Scholar 

  19. John, S. et al. The something about silencing protein, Sas3, is the catalytic subunit of NuA3, a yTAF(II)30-containing HAT complex that interacts with the Spt1a6 subunit of the yeast CP (Cdc68/Pob3)–FACT complex. Genes Dev. 14, 1196–1208 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Wittschieben, B. O. et al. A novel histone acetyltransferase is an integral subunit of elongating RNA polymerase II holoenzyme. Mol. Cell 4, 123–128 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hassan, A. H. et al. Function and selectivity of bromodomains in anchoring chromatin-modifying complexes to promoter nucleosomes. Cell 111, 369–379 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. Keogh, M. C. et al. Cotranscriptional Set1b methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 123, 593–605 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Carrozza, M. J. et al. Histone H3 methylation by Set1b directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123, 581–592 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. 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 

  38. Coté, J. & Richard, S. Tudor domains bind symmetrical dimethylated arginines. J. Biol. Chem. 280, 28476–28483 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006). References 39–41 provide structural evidence that the PHD fingers can recognize and bind H3K4 trimethylation.

    Article  CAS  PubMed  Google Scholar 

  42. Reid, J. L., Moqtaderi, Z. & Struhl, K. Eaf3 regulates the global pattern of histone acetylation in Saccharomyces cerevisiae. Mol. Cell. Biol. 24, 757–764 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wu, P. Y., Ruhlmann, C., Winston, F. & Schultz, P. Molecular architecture of the S. cerevisiae SAGA complex. Mol. Cell 15, 199–208 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Kusch, T. et al. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science 306, 2084–2087 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Suka, N., Luo, K. & Grunstein, M. Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin. Nature Genet. 32, 378–383 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Kouzarides, T. Acetylation: a regulatory modification to rival phosphorylation? EMBO J. 19, 1176–1179 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet. 37, 391–400 (2005). Shows the importance of H4K16 acetylation as a predictor of human cancer.

    Article  CAS  PubMed  Google Scholar 

  48. Shogren-Knaak, M. et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006). A key paper that shows the importance of a single histone modification in modulating both higher-order chromatin structure and functional interactions between a non-histone protein and the chromatin fibre.

    Article  CAS  PubMed  Google Scholar 

  49. Akhtar, A. & Becker, P. B. Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Mol. Cell 5, 367–375 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Hilfiker, A., Hilfiker-Kleiner, D., Pannuti, A. & Lucchesi, J. C. mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. EMBO J. 16, 2054–2060 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Smith, E. R. et al. A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16. Mol. Cell. Biol. 25, 9175–9188 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Osada, S. et al. The yeast SAS (something about silencing) protein complex contains a MYST-type putative acetyltransferase and functions with chromatin assembly factor ASF1. Genes Dev. 15, 3155–3168 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Meijsing, S. H. & Ehrenhofer-Murray, A. E. The silencing complex SAS-I links histone acetylation to the assembly of repressed chromatin by CAF-I and Asf1 in Saccharomyces cerevisiae. Genes Dev. 15, 3169–3182 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kimura, A., Umehara, T. & Horikoshi, M. Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing. Nature Genet. 32, 370–377 (2002).

    Article  PubMed  Google Scholar 

  55. Shia, W. J. et al. Characterization of the yeast trimeric-SAS acetyltransferase complex. J. Biol. Chem. 280, 11987–11994 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Shia, W. J., Li, B. & Workman, J. SAS-mediated acetylation of histone H4 lysine 16 is required for H2A.Z incorporation at telomeres in Saccharomyces cerevisiae. Genes Dev. 20 2507–2512 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Smith, E. R. et al. The Drosophila MSL complex acetylates histone H4 at lysine 16, a chromatin modification linked to dosage compensation. Mol. Cell. Biol. 20, 312–318 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kelley, R. L. et al. Epigenetic spreading of the Drosophila dosage compensation complex from roX RNA genes into flanking chromatin. Cell 98, 513–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Sass, G. L., Pannuti, A. & Lucchesi, J. C. Male-specific lethal complex of Drosophila targets activated regions of the X chromosome for chromatin remodeling. Proc. Natl Acad. Sci. USA 100, 8287–8291 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gu, W., Szauter, P. & Lucchesi, J. C. Targeting of MOF, a putative histone acetyl transferase, to the X chromosome of Drosophila melanogaster. Dev. Genet. 22, 56–64 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Dou, Y. et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121, 873–885 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Tuteja, N. & Tuteja, R. Unraveling DNA repair in human: molecular mechanisms and consequences of repair defect. Crit. Rev. Biochem. Mol. Biol. 36, 261–290 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Loizou, J. I. et al. Epigenetic information in chromatin: the code of entry for DNA repair. Cell Cycle 5, 696–701 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Allard, S., Masson, J. Y. & Coté, J. Chromatin remodeling and the maintenance of genome integrity. Biochim. Biophys. Acta 1677, 158–164 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. West, S. C. & Connolly, B. Biological roles of the Escherichia coli RuvA, RuvB and RuvC proteins revealed. Mol. Microbiol. 6, 2755–2759 (1992).

    Article  CAS  PubMed  Google Scholar 

  66. Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Jin, J. et al. In and out: histone variant exchange in chromatin. Trends Biochem. Sci. 30, 680–687 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Bird, A. W. et al. Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature 419, 411–415 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Choy, J. S. & Kron, S. J. NuA4 subunit Yng2 function in intra-S-phase DNA damage response. Mol. Cell. Biol. 22, 8215–8225 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Downs, J. A. et al. Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. Mol. Cell 16, 979–90 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Utley, R. T., Lacoste, N., Jobin-Robitaille, O., Allard, S. & Coté, J. Regulation of NuA4 histone acetyltransferase activity in transcription and DNA repair by phosphorylation of histone H4. Mol. Cell. Biol. 25, 8179–8190 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Brand, M. et al. UV-damaged DNA-binding protein in the TFTC complex links DNA damage recognition to nucleosome acetylation. EMBO J. 20, 3187–3196 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Yu, Y. & Waters, R. Histone acetylation, chromatin remodelling and nucleotide excision repair: hint from the study on MFA2 in Saccharomyces cerevisiae. Cell Cycle 4, 1043–1045 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Das, B. K. et al. Characterization of a protein complex containing spliceosomal proteins SAPs 49, 130, 145, and 155. Mol. Cell. Biol. 19, 6796–6802 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yu, Y., Teng, Y., Liu, H., Reed, S. H. & Waters, R. UV irradiation stimulates histone acetylation and chromatin remodeling at a repressed yeast locus. Proc. Natl Acad. Sci. USA 102, 8650–8655 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Teng, Y., Yu, Y. & Waters, R. The Saccharomyces cerevisiae histone acetyltransferase Gcn5 has a role in the photoreactivation and nucleotide excision repair of UV-induced cyclobutane pyrimidine dimers in the MFA2 gene. J. Mol. Biol. 316, 489–499 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Poux, A. N. & Marmorstein, R. Molecular basis for Gcn5/PCAF histone acetyltransferase selectivity for histone and nonhistone substrates. Biochemistry 42, 14366–14374 (2003). Shows the ability of the catalytic domain of Gcn5 to accommodate a number of substrates, through the fine tuning of intermolecular and intramolecular interactions.

    Article  CAS  PubMed  Google Scholar 

  79. Brand, M., Leurent, C., Mallouh, V., Tora, L. & Schultz, P. Three-dimensional structures of the TAFII-containing complexes TFIID and TFTC. Science 286, 2151–2153 (1999). This is the first description of the three-dimensional structure and basis of recognition of a macromolecular complex that contains a HAT.

    Article  CAS  PubMed  Google Scholar 

  80. Dornan, D., Shimizu, H., Perkins, N. D. & Hupp, T. R. DNA-dependent acetylation of p53 by the transcription coactivator p300. J. Biol. Chem. 278, 13431–13441 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Dornan, D. et al. Interferon regulatory factor 1 binding to p300 stimulates DNA-dependent acetylation of p53. Mol. Cell. Biol. 24, 10083–10098 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lo, W. S. et al. Snf1 — a histone kinase that works in concert with the histone acetyltransferase Gcn5 to regulate transcription. Science 293, 1142–1146 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Grunstein, M. Histone acetylation in chromatin structure and transcription. Nature 389, 349–352 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  86. Turner, B. M. Histone acetylation and an epigenetic code. Bioessays 22, 836–845 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Turner, B. M. Memorable transcription. Nature Cell Biol. 5, 390–393 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  90. Pray-Grant, M. G., Daniel, J. A., Schieltz, D., Yates, J. R. 3rd & Grant, P. A. Chd1 chromodomain links histone H3 methylation with SAGA- and SLIK-dependent acetylation. Nature 433, 434–438 (2005). Links histone methylation to histone acetylation through Chd1, identifying it as the first H3K4 methyl-binding protein.

    Article  CAS  PubMed  Google Scholar 

  91. Martin, D. G., Grimes, D. E., Baetz, K. & Howe, L. Methylation of histone H3 mediates the association of the NuA3 histone acetyltransferase with chromatin. Mol. Cell. Biol. 26, 3018–3028 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Rodriguez-Navarro, S. et al. Sus1, a functional component of the SAGA histone acetylase complex and the nuclear pore-associated mRNA export machinery. Cell 116, 75–86 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Henry, K. W. et al. Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev. 17, 2648–2663 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Daniel, J. A. et al. Deubiquitination of histone H2B by a yeast acetyltransferase complex regulates transcription. J. Biol. Chem. 279, 1867–1871 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Powell, D. W. et al. Cluster analysis of mass spectrometry data reveals a novel component of SAGA. Mol. Cell. Biol. 24, 7249–7259 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tran, H. G., Steger, D. J., Iyer, V. R. & Johnson, A. D. The chromo domain protein Chd1p from budding yeast is an ATP-dependent chromatin-modifying factor. EMBO J. 19, 2323–2331 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Perry, J. The Epc-N domain: a predicted protein–protein interaction domain found in select chromatin associated proteins. BMC Genomics 7, 6 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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. 7871–7879 (2006). References 91 and 99 demonstrate the interplay between the NuA3 HAT complex and the Set1a and Set1b histone methyltransferases in regulating Gcn5-independent H3 acetylation, as well as the importance of the PHD finger of the yeast inhibitor of growth protein, Yng1.

  100. Nathan, D. et al. Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. Genes Dev. 20, 966–976 (2006). This is the first demonstration of a histone mark in S. cerevisiae that functions in transcriptional repression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Shiio, Y. & Eisenman, R. N. Histone sumoylation is associated with transcriptional repression. Proc. Natl Acad. Sci. USA 100, 13225–13230 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Desterro, J. M., Rodriguez, M. S. & Hay, R. T. SUMO-1 modification of IκBα inhibits NF-κB activation. Mol. Cell 2, 233–239 (1998).

    Article  CAS  PubMed  Google Scholar 

  103. Verdin, E., Dequiedt, F. & Kasler, H. G. Class II histone deacetylases: versatile regulators. Trends Genet. 19, 286–293 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Marzluff, W. F. Jr & McCarty, K. S. Two classes of histone acetylation in developing mouse mammary gland. J. Biol. Chem. 245, 5635–5642 (1970).

    CAS  PubMed  Google Scholar 

  105. Kuo, M. H. & Allis, C. D. Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays 20, 615–626 (1998).

    Article  CAS  PubMed  Google Scholar 

  106. Workman, J. L. & Kingston, R. E. Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu. Rev. Biochem. 67, 545–579 (1998).

    Article  CAS  PubMed  Google Scholar 

  107. Yang, X.-J., Ogryzko, V. V., Nichikawa, J.-I., Howard, B. H. & Nakatani, Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382, 319–324 (1996).

    Article  CAS  PubMed  Google Scholar 

  108. Mizzen, C. A. et al. The TAF(II)250 subunit of TFIID has histone acetyltransferase activity. Cell 87, 1261–1270 (1996).

    Article  CAS  PubMed  Google Scholar 

  109. Chen, H. et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90, 569–580 (1997).

    Article  CAS  PubMed  Google Scholar 

  110. van der Schalie, E. & Green, C. B. Cryptochromes. Curr. Biol. 15, R785 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Kondratov, R. V. et al. BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes Dev. 17, 1921–1932 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kondratov, R. V., Shamanna, R. K., Kondratova, A. A., Gorbacheva, V. Y. & Antoch, M. P. Dual role of the CLOCK/BMAL1 circadian complex in transcriptional regulation. FASEB J. 20, 530–532 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Kondratov, R. V. et al. Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES. Cell Cycle 5, 890–895 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Vidanes, G. M., Bonilla, C. Y. & Toczyski, D. P. Complicated tails: histone modifications and the DNA damage response. Cell 121, 973–976 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Qin, S. & Parthun, M. R. Recruitment of the type B histone acetyltransferase Hat1ap to chromatin is linked to DNA double-strand breaks. Mol. Cell. Biol. 26, 3649–3658 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Clements, A. et al. Structural basis for histone and phosphohistone binding by the GCN5 histone acetyltransferase. Mol. Cell 12, 461–473 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Guelman, S. et al. The essential gene wda encodes a WD40 repeat subunit of Drosophila SAGA required for histone H3 acetylation. Mol. Cell. Biol. 26, 7178–7189 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Guelman, S. et al. Host cell factor and an uncharacterized SANT domain protein are stable components of ATAC, a novel dAda2A/dGcn5-containing histone acetyltransferase complex in Drosophila. Mol. Cell. Biol. 26, 871–882 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Watson, J. D. & Crick, F. H. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171, 737–738 (1953).

    Article  CAS  PubMed  Google Scholar 

  120. Nirenberg, M. W., Matthaei, J. H., Jones, O. W., Martin, R. G. & Barondes, S. H. Approximation of genetic code via cell-free protein synthesis directed by template RNA. Fed. Proc. 22, 55–61 (1963).

    CAS  PubMed  Google Scholar 

  121. Crick, F. H., Barnett, L., Brenner, S. & Watts-Tobin, R. J. General nature of the genetic code for proteins. Nature 192, 1227–1232 (1961).

    Article  CAS  PubMed  Google Scholar 

  122. Kornberg, R. Chromatin structure: a repeating unit of histones and DNA. Science 184, 868–871 (1974).

    Article  CAS  PubMed  Google Scholar 

  123. Brownell, J. E. & Allis, C. D. An activity gel assay detects a single, catalytically active histone acetyltransferase subunit in Tetrahymena macronuclei. Proc. Natl Acad. Sci. USA 92, 6364–6368 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Parthun, M. R., Widom, J. & Gottschling, D. E. The major cytoplasmic histone acetyltransferase in yeast: links to chromatin replication and histone metabolism. Cell 87, 85–94 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. 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. Nature 389, 251–260 (1997).

    Article  CAS  PubMed  Google Scholar 

  126. Rojas, J. R. et al. Structure of Tetrahymena GCN5 bound to coenzyme A and a histone H3 peptide. Nature 401, 93–98 (1999).

    Article  CAS  PubMed  Google Scholar 

  127. Trievel, R. C. et al. Crystal structure and mechanism of histone acetylation of the yeast GCN5 transcriptional coactivator. Proc. Natl Acad. Sci. USA 96, 8931–8936 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lau, O. D. et al. HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. Mol. Cell 5, 589–595 (2000).

    Article  CAS  PubMed  Google Scholar 

  129. Turner, B. M. Decoding the nucleosome. Cell 75, 5–8 (1993).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to L. Krom, K. Smith, V. Weake, B. Li, P. Prochasson and M. Carey for helpful discussions and critical reading of the manuscript. We thank W.-J. Shia for the concept in Figure 1 and B. Li and B. Geisbrecht for assistance with Figure 2. We apologize to our colleagues for not being able to quote all references owing to space limitations. K.K.L. was supported by a postdoctoral fellowship from the Damon Runyon Cancer Research Foundation. Research in the Workman laboratory is supported by the US National Institutes of Health.

Author information

Authors and Affiliations

  1. Stowers Institute, 1000 East 50th Street, Kansas City, 64110, Missouri, USA

    Kenneth K. Lee & Jerry L. Workman

Authors
  1. Kenneth K. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerry L. Workman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jerry L. Workman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

RCSB Protein Data Bank

1PU9

1PUA

1Q2C

1Q2D

Saccharomyces Genome Database

Elp3

Gcn5

Hat1a

Hpa2

Nut1a

Sas2

Sas3

Glossary

Bromodomain

An evolutionarily conserved domain that has been shown to bind to acetylated residues.

Chromodomain

A conserved structural motif that is common to some chromosomal proteins. It interacts with chromatin by binding to methylated lysine residues in histone proteins.

WD40 repeat

A poorly conserved repeat sequence of 40–60 amino acids, which usually ends with tryptophan and aspartic acid (WD). Several consecutive repeats fold into a circular structure, a so-called β-propeller, in which each blade is a four-stranded β-sheet. This domain is found in proteins of various functions.

Tudor domain

A domain first identified in the Drosophila melanogaster Tudor protein. Originally identified as an RNA-binding motif, it has also been shown to bind methyl arginine residues and methylated histones.

PHD finger

(Plant homeodomain). A ∼50-amino-acid motif found mainly in proteins that function in eukaryotic transcription. The characteristic sequence feature is a conserved Cys4-His-Cys3 zinc-binding motif.

bHLH–PAS domain

A structural motif that is characterized by two helices connected by a loop. Transcription factors that contain this domain are typically dimeric, each with one helix that contains basic amino-acid residues that facilitate DNA binding. Basic helix–loop–helix (bHLH) proteins typically bind to a consensus sequence, CANNTG, which is known as an E-box. The PAS (PER–ARNT–SIM) domain mediates interactions between transcription factors, and most PAS-domain-containing proteins also contain a bHLH domain.

E-box

A DNA location with the consensus sequence CANNTG. E-boxes have a regulatory role in the control of transcription. They bind to basic helix–loop–helix (bHLH)-type transcription factors. Binding specificity is determined by the specific bHLH heterodimer or homodimer combination and by the specific nucleotides at the third and fourth position of the E-box sequence.

Nucleotide excision repair

A DNA-repair process, in which a small region of the DNA strand that surrounds the UV-induced DNA damage is recognized, removed and replaced.

Double-strand break (DSB) repair

A group of DNA-repair processes that includes homologous recombination and non-homologous end-joining; both processes recognize and repair the DNA double-strand break.

NAD-dependent histone deacetylase

An enzyme that catalyses the NAD-dependent removal of an acetyl group from lysine residues in histones.

Heterochromatin

A highly condensed and transcriptionally less active form of chromatin that occurs at defined sites such as centromeres, silencer DNA elements or telomeres.

Dosage compensation

A process by which the expression of sex-linked genes is equalized in species in which males and females differ in the number of sex chromosomes. In Drosophila melanogaster dosage compensation is achieved by hypertranscription of the single male X chromosome.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, K., Workman, J. Histone acetyltransferase complexes: one size doesn't fit all. Nat Rev Mol Cell Biol 8, 284–295 (2007). https://doi.org/10.1038/nrm2145

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2145

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