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:

The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men

Key Points

  • In the past decade, protein Lys acetylation has emerged as a major post-translational modification that occurs even in bacteria. This modification not only regulates chromatin-templated nuclear processes, but also controls classical metabolism, cytoskeleton dynamics, apoptosis, protein folding and cellular signalling in the cytoplasm.

  • Lys deacetylases, the enzymes that are responsible for reversing this modification, are divided into the Rpd3/Hda1 (or classical) and sirtuin families, with the classical family having 11 members in mammals. These members are referred to as histone deacetylases (HDAC) 1–11.

  • HDAC1, HDAC2 and HDAC3 are deacetylase subunits of multiprotein complexes that are crucial for chromatin modification and epigenetic landscaping. These complexes comprise subunits that are required for interplay with other chromatin modifications such as DNA and histone methylation, as well as with ATP-dependent chromatin remodelling.

  • HDAC4, HDAC5, HDAC7 and HDAC9 are novel signal transducers that are tightly regulated by phosphorylation-dependent nucleocytoplasmic trafficking. Conceptually, they are similar to the cytokine-stimulated STAT and TGFβ-regulated SMAD signal-responsive transcription factors.

  • By binding to ubiquitin and deacetylating α-tubulin, cortactin and HSP90, HDAC6 regulates various cytoplasmic processes including cytoskeleton dynamics, ciliogenesis, aggresome formation, autophagy, nuclear receptor maturation and, possibly, endocytosis of Tyr kinase receptors.

  • HDAC inhibitors are promising therapeutic agents for cancer and other major diseases, as evidenced by the recent approval of one such inhibitor for the treatment of cutaneous T-cell lymphoma.

Abstract

Protein lysine deacetylases have a pivotal role in numerous biological processes and can be divided into the Rpd3/Hda1 and sirtuin families, each having members in diverse organisms including prokaryotes. In vertebrates, the Rpd3/Hda1 family contains 11 members, traditionally referred to as histone deacetylases (HDAC) 1–11, which are further grouped into classes I, II and IV. Whereas most class I HDACs are subunits of multiprotein nuclear complexes that are crucial for transcriptional repression and epigenetic landscaping, class II members regulate cytoplasmic processes or function as signal transducers that shuttle between the cytoplasm and the nucleus. Little is known about class IV HDAC11, although its evolutionary conservation implies a fundamental role in various organisms.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Domain organization of classical HDACs from yeast and humans.
Figure 2: HDAC4 and other class IIa homologues as signal transducers.
Figure 3: HDAC6 is a major deacetylase in the cytoplasm.

Similar content being viewed by others

References

  1. Gershey, E. L., Vidali, G. & Allfrey, V. G. Chemical studies of histone acetylation. The occurrence of ε-N-acetyllysine in the f2a1 histone. J. Biol. Chem. 243, 5018–5022 (1968).

    CAS  PubMed  Google Scholar 

  2. Inoue, A. & Fujimoto, D. Enzymatic deacetylation of histone. Biochem. Biophys. Res. Commun. 36, 146–150 (1969).

    CAS  PubMed  Google Scholar 

  3. Candido, E. P., Reeves, R. & Davie, J. R. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 14, 105–113 (1978).

    CAS  PubMed  Google Scholar 

  4. Sealy, L. & Chalkley, R. The effect of sodium butyrate on histone modification. Cell 14, 115–121 (1978).

    CAS  PubMed  Google Scholar 

  5. Vidali, G., Boffa, L. C., Bradbury, E. M. & Allfrey, V. G. Butyrate suppression of histone deacetylation leads to accumulation of multiacetylated forms of histones H3 and H4 and increased DNase I sensitivity of the associated DNA sequences. Proc. Natl Acad. Sci. USA 75, 2239–2243 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Yoshida, M., Kijima, M., Akita, M. & Beppu, T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J. Biol. Chem. 265, 17174–17179 (1990). Identified the first specific HDAC inhibitor and linked HDAC inhibition to cell growth arrest.

    CAS  PubMed  Google Scholar 

  7. Taunton, J., Hassig, C. A. & Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408–411 (1996). Affinity purification and identification of the first HDAC, supporting the link between gene silencing and histone deacetylation.

    CAS  PubMed  Google Scholar 

  8. Vidal, M. & Gaber, R. F. RPD3 encodes a second factor required to achieve maximum positive and negative transcriptional states in Saccharomyces cerevisiae. Mol. Cell. Biol. 11, 6317–6327 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang, W. M., Inouye, C., Zeng, Y., Bearss, D. & Seto, E. Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3. Proc. Natl Acad. Sci. USA 93, 12845–12850 (1996). First report on the direct physical link of Rpd3 to a sequence-specific transcriptional repressor.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Rundlett, S. E. et al. HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription. Proc. Natl Acad. Sci. USA 93, 14503–14508 (1996). Discovery of Hda1 and Rpd3 as deacetylase subunits of two multiprotein complexes and identification of related proteins in bacteria.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Grozinger, C. M. & Schreiber, S. L. Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. Chem. Biol. 9, 3–16 (2002).

    CAS  PubMed  Google Scholar 

  12. Haigis, M. C. & Guarente, L. P. Mammalian sirtuins — emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20, 2913–2921 (2006).

    CAS  PubMed  Google Scholar 

  13. de Ruijter, A. J., van Gennip, A. H., Caron, H. N., Kemp, S. & van Kuilenburg, A. B. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J. 370, 737–749 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Khochbin, S., Verdel, A., Lemercier, C. & Seigneurin-Berny, D. Functional significance of histone deacetylase diversity. Curr. Opin. Genet. Dev. 11, 162–166 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Gregoretti, I. V., Lee, Y. M. & Goodson, H. V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 338, 17–31 (2004). An elegant phylogenetic analysis about different groups of HDACs.

    CAS  PubMed  Google Scholar 

  17. Goldberg, A. D., Allis, C. D. & Bernstein, E. Epigenetics: a landscape takes shape. Cell 128, 635–638 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  19. Marks, P. A. & Breslow, R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nature Biotechnol. 25, 84–90 (2007).

    CAS  Google Scholar 

  20. Butler, R. & Bates, G. P. Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nature Rev. Neurosci. 7, 784–796 (2006).

    CAS  Google Scholar 

  21. Nicolas, E. et al. Distinct roles of HDAC complexes in promoter silencing, antisense suppression and DNA damage protection. Nature Struct. Mol. Biol. 14, 372–380 (2007).

    CAS  Google Scholar 

  22. Sengupta, N. & Seto, E. Regulation of histone deacetylase activities. J. Cell. Biochem. 93, 57–67 (2004).

    CAS  PubMed  Google Scholar 

  23. Zhang, X. et al. Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Genes Dev. 19, 827–839 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee, H., Rezai-Zadeh, N. & Seto, E. Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. Mol. Cell. Biol. 24, 765–773 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Vannini, A. et al. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc. Natl Acad. Sci. USA 101, 15064–15069 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang, X. J. & Grégoire, S. Class II histone deacetylases: from sequence to function, regulation and clinical implication. Mol. Cell. Biol. 25, 2873–2884 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Han, A., He, J., Wu, Y., Liu, J. O. & Chen, L. Mechanism of recruitment of class II histone deacetylases by myocyte enhancer factor-2. J. Mol. Biol. 345, 91–102 (2005).

    CAS  PubMed  Google Scholar 

  28. Fischle, W. et al. Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol. Cell 9, 45–57 (2002).

    CAS  PubMed  Google Scholar 

  29. Lamb, N. et al. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl Acad. Sci. USA 104, 17355–17340 (2007).

    Google Scholar 

  30. Moreth, K. et al. An active site tyrosine residue is essential for amidohydrolase but not for esterase activity of a class 2 histone deacetylase-like bacterial enzyme. Biochem. J. 401, 659–665 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Boyault, C., Sadoul, K., Pabion, M. & Khochbin, S. HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene 26, 5468–5476 (2007).

    CAS  PubMed  Google Scholar 

  32. Gao, L., Cueto, M. A., Asselbergs, F. & Atadja, P. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 277, 25748–25755 (2002).

    CAS  PubMed  Google Scholar 

  33. Somoza, J. R. et al. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 12, 1325–1334 (2004).

    CAS  PubMed  Google Scholar 

  34. Finnin, M. S. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188–193 (1999).

    CAS  PubMed  Google Scholar 

  35. Nielsen, T. K., Hildmann, C., Dickmanns, A., Schwienhorst, A. & Ficner, R. Crystal structure of a bacterial class 2 histone deacetylase homologue. J. Mol. Biol. 354, 107–120 (2005).

    CAS  PubMed  Google Scholar 

  36. Boyer, L. A., Latek, R. R. & Peterson, C. L. The SANT domain: a unique histone-tail-binding module? Nature Rev. Mol. Cell. Biol. 5, 158–163 (2004).

    CAS  Google Scholar 

  37. Kasten, M. M., Dorland, S. & Stillman, D. J. A large protein complex containing the yeast Sin3p and Rpd3p transcriptional regulators. Mol. Cell. Biol. 17, 4852–4858 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Keogh, M. C. et al. Cotranscriptional Set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 123, 593–605 (2005).

    CAS  PubMed  Google Scholar 

  39. 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 

  40. Colina, A. R. & Young, D. Raf60, a novel component of the Rpd3 histone deacetylase complex required for Rpd3 activity in Saccharomyces cerevisiae. J. Biol. Chem. 280, 42552–42556 (2005).

    CAS  PubMed  Google Scholar 

  41. Kadosh, D. & Struhl, K. Repression by Ume6 involves recruitment of a complex containing Sin3 corepressor and Rpd3 histone deacetylase to target promoters. Cell 89, 365–371 (1997).

    CAS  PubMed  Google Scholar 

  42. 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 

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

    CAS  PubMed  Google Scholar 

  44. Ahringer, J. NuRD and SIN3 histone deacetylase complexes in development. Trends Genet. 16, 351–356 (2000).

    CAS  PubMed  Google Scholar 

  45. 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 

  46. Le Guezennec, X., Vermeulen, M. & Stunnenberg, H. G. Molecular characterization of Sin3 PAH-domain interactor specificity and identification of PAH partners. Nucleic Acids Res. 34, 3929–3937 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Denslow, S. A. & Wade, P. A. The human Mi-2/NuRD complex and gene regulation. Oncogene 26, 5433–5438 (2007).

    CAS  PubMed  Google Scholar 

  48. Klose, R. J. & Bird, A. P. Genomic DNA methylation: the mark and its mediators. Trends Biochem. Sci. 31, 89–97 (2006).

    CAS  PubMed  Google Scholar 

  49. Andres, M. E. et al. CoREST: a functional corepressor required for regulation of neural-specific gene expression. Proc. Natl Acad. Sci. USA 96, 9873–9878 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. You, A., Tong, J. K., Grozinger, C. M. & Schreiber, S. L. CoREST is an integral component of the CoREST–human histone deacetylase complex. Proc. Natl Acad. Sci. USA 98, 1454–1458 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Humphrey, G. W. et al. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276, 6812–6824 (2001).

    Google Scholar 

  52. 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 

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

    CAS  PubMed  Google Scholar 

  54. Lee, M. G., Wynder, C., Cooch, N. & Shiekhattar, R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437, 432–435 (2005).

    CAS  PubMed  Google Scholar 

  55. Lee, M. G. et al. Functional interplay between histone demethylase and deacetylase enzymes. Mol. Cell. Biol. 26, 6395–6402 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Wen, Y. D. et al. The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 97, 7202–7207 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang, J., Kalkum, M., Chait, B. T. & Roeder, R. G. The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Mol. Cell 9, 611–623 (2002).

    CAS  PubMed  Google Scholar 

  58. Karagianni, P. & Wong, J. HDAC3: taking the SMRT-N-CoRrect road to repression. Oncogene 26, 5439–5449 (2007).

    CAS  PubMed  Google Scholar 

  59. Guenther, M. G. et al. A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Genes Dev. 14, 1048–1057 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Li, J. et al. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J. 19, 4342–4350 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Underhill, C., Qutob, M. S., Yee, S. P. & Torchia, J. A novel nuclear receptor corepressor complex, N-CoR, contains components of the mammalian SWI/SNF complex and the corepressor KAP-1. J. Biol. Chem. 275, 40463–40470 (2000).

    CAS  PubMed  Google Scholar 

  62. Guenther, M. G., Barak, O. & Lazar, M. A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 21, 6091–6101 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Wu, J., Carmen, A. A., Kobayashi, R., Suka, N. & Grunstein, M. HDA2 and HDA3 are related proteins that interact with and are essential for the activity of the yeast histone deacetylase HDA1. Proc. Natl Acad. Sci. USA 98, 4391–4396 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Sugiyama, T. et al. SHREC, an effector complex for heterochromatic transcriptional silencing. Cell 128, 491–504 (2007).

    CAS  PubMed  Google Scholar 

  65. Grozinger, C. M. & Schreiber, S. L. Regulation of histone deacetylase 4 and 5 transcriptional activity by 14-3-3-dependent cellular localization. Proc. Natl Acad. Sci. USA 97, 7835–7840 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Paroni, G. et al. PP2A regulates HDAC4 nuclear import. Mol. Biol. Cell 19, 655–667 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Seigneurin-Berny, D. et al. Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways. Mol. Cell. Biol. 21, 8035–8044 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhang, X. et al. HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol. Cell 27, 197–213 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. McKinsey, T. A., Zhang, C. L., Lu, J. & Olson, E. N. Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408, 106–111 (2000). First report on the kinase-mediated nuclear export of a class IIa HDAC.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. McKinsey, T. A. & Olson, E. N. Cardiac histone acetylation — therapeutic opportunities abound. Trends Genet. 20, 206–213 (2004).

    CAS  PubMed  Google Scholar 

  71. Martin, M., Kettmann, R. & Dequiedt, F. Class IIa histone deacetylases: regulating the regulators. Oncogene 26, 5450–5467 (2007).

    CAS  PubMed  Google Scholar 

  72. Zhang, C. L., McKinsey, T. A. & Olson, E. N. The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc. Natl Acad. Sci. USA 98, 7354–7359 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. van der Linden, A. M., Nolan, K. M. & Sengupta, P. KIN-29 SIK regulates chemoreceptor gene expression via an MEF2 transcription factor and a class II HDAC. EMBO J. 26, 358–370 (2007).

    CAS  PubMed  Google Scholar 

  74. Li, X., Song, S., Liu, Y., Ko, S. H. & Kao, H. Y. Phosphorylation of the histone deacetylase 7 modulates its stability and association with 14-3-3 proteins. J. Biol. Chem. 279, 34201–34208 (2004).

    CAS  PubMed  Google Scholar 

  75. Potthoff, M. J. et al. Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers. J. Clin. Invest. 117, 2459–2467 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Linseman, D. A. et al. Inactivation of the myocyte enhancer factor-2 repressor histone deacetylase-5 by endogenous Ca2+/calmodulin-dependent kinase II promotes depolarization-mediated cerebellar granule neuron survival. J. Biol. Chem. 278, 41472–41481 (2003).

    CAS  PubMed  Google Scholar 

  77. Vega, R. B. et al. Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5. Mol. Cell. Biol. 24, 8374–8385 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Parra, M., Kasler, H., McKinsey, T. A., Olson, E. N. & Verdin, E. Protein kinase D1 phosphorylates HDAC7 and induces its nuclear export after TCR activation. J. Biol. Chem. 280, 13762–13770 (2005).

    CAS  PubMed  Google Scholar 

  79. Dequiedt, F. et al. Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor-induced Nur77 expression and apoptosis. J. Exp. Med. 201, 793–804 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Chang, S., Bezprozvannaya, S., Li, S. & Olson, E. N. An expression screen reveals modulators of class II histone deacetylase phosphorylation. Proc. Natl Acad. Sci. USA 102, 8120–8125 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Berdeaux, R. et al. SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nature Med. 13, 597–603 (2007).

    CAS  PubMed  Google Scholar 

  82. Kim, M. A. et al. Identification of novel substrates for human checkpoint kinase Chk1 and Chk2 through genome-wide screening using a consensus Chk phosphorylation motif. Exp. Mol. Med. 39, 205–212 (2007).

    CAS  PubMed  Google Scholar 

  83. Parra, M., Mahmoudi, T. & Verdin, E. Myosin phosphatase dephosphorylates HDAC7, controls its nucleocytoplasmic shuttling, and inhibits apoptosis in thymocytes. Genes Dev. 21, 638–643 (2007). Shows that a PP1 phosphatase complex is directly involved in controlling the nucleocytoplasmic trafficking of HDAC7.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Sucharov, C. C., Langer, S., Bristow, M. & Leinwand, L. Shuttling of HDAC5 in H9C2 cells regulates YY1 function through CaMKIV/PKD and PP2A. Am. J. Physiol. Cell Physiol. 291, C1029–C1037 (2006).

    CAS  PubMed  Google Scholar 

  85. Illi, B. et al. Nitric oxide modulates chromatin folding in human endothelial cells via protein phosphatase 2A activation and class II histone deacetylases nuclear shuttling. Circ. Res. 102, 51–58 (2007).

    PubMed  Google Scholar 

  86. Kirsh, O. et al. The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J. 21, 2682–2691 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Petrie, K. et al. The histone deacetylase 9 gene encodes multiple protein isoforms. J. Biol. Chem. 278, 16059–16072 (2003).

    CAS  PubMed  Google Scholar 

  88. Tatham, M. H. et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J. Biol. Chem. 276, 35368–35374 (2001).

    CAS  PubMed  Google Scholar 

  89. Paroni, G. et al. Caspase-dependent regulation of histone deacetylase 4 nuclear-cytoplasmic shuttling promotes apoptosis. Mol. Biol. Cell 15, 2804–2818 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Liu, F., Dowling, M., Yang, X. J. & Kao, G. D. Caspase-mediated specific cleavage of human histone deacetylase 4. J. Biol. Chem. 279, 34537–34546 (2004).

    CAS  PubMed  Google Scholar 

  91. Chen, J. F. et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nature Genet. 38, 228–233 (2006).

    CAS  PubMed  Google Scholar 

  92. Haberland, M. et al. Regulation of HDAC9 gene expression by MEF2 establishes a negative-feedback loop in the transcriptional circuitry of muscle differentiation. Mol. Cell. Biol. 27, 518–525 (2007).

    CAS  PubMed  Google Scholar 

  93. Hubbert, C. et al. HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458 (2002). First report on the unexpected α-tubulin deacetylase activity of HDAC6.

    CAS  PubMed  Google Scholar 

  94. Matsuyama, A. et al. In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J. 21, 6820–6831 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhang, Y. et al. HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO J. 22, 1168–1179 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Tran, A. D. et al. HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions. J. Cell Sci. 120, 1469–1479 (2007).

    CAS  PubMed  Google Scholar 

  97. Serrador, J. M. et al. HDAC6 deacetylase activity links the tubulin cytoskeleton with immune synapse organization. Immunity 20, 417–428 (2004).

    CAS  PubMed  Google Scholar 

  98. Reed, N. A. et al. Microtubule acetylation promotes kinesin-1 binding and transport. Curr. Biol. 16, 2166–2172 (2006).

    CAS  PubMed  Google Scholar 

  99. Dompierre, J. P. et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J. Neurosci. 27, 3571–3583 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Pugacheva, E. N., Jablonski, S. A., Hartman, T. R., Henske, E. P. & Golemis, E. A. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129, 1351–1363 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Linding, R. et al. Systematic discovery of in vivo phosphorylation networks. Cell 129, 1415–1426 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Kovacs, J. J. et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601–607 (2005).

    CAS  PubMed  Google Scholar 

  103. Bali, P. et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 280, 26729–26734 (2005).

    CAS  PubMed  Google Scholar 

  104. Murphy, P. J., Morishima, Y., Kovacs, J. J., Yao, T. P. & Pratt, W. B. Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone. J. Biol. Chem. 280, 33792–33799 (2005).

    CAS  PubMed  Google Scholar 

  105. Scroggins, B. T. et al. An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol. Cell 25, 151–159 (2007). References 103–105 demonstrate that HDAC6 binds to and deacetylates HSP90, thereby regulating its chaperone activity towards client proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Kopito, R. R. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10, 524–530 (2000).

    CAS  PubMed  Google Scholar 

  107. Kawaguchi, Y. et al. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727–738 (2003). Demonstrates that HDAC6 has a key role in aggresome formation, thereby linking this deacetylase to the cellular management of misfolded proteins.

    CAS  PubMed  Google Scholar 

  108. Boyault, C. et al. HDAC6-p97/VCP controlled polyubiquitin chain turnover. EMBO J. 25, 3357–3366 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Pandey, U. B. et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 859–863 (2007).

    CAS  PubMed  Google Scholar 

  110. Iwata, A., Riley, B. E., Johnston, J. A. & Kopito, R. R. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J. Biol. Chem. 280, 40282–40292 (2005). References 109 and 110 report the unexpected link of HDAC6 to autophagy.

    CAS  PubMed  Google Scholar 

  111. Boyault, C. et al. HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev. 21, 2172–2181 (2007). An elegant study linking HDAC6 to the activation of the transcription factor HSF1 in response to cytotoxic protein aggregates.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Kwon, S., Zhang, Y. & Matthias, P. The deacetylase HDAC6 is a novel essential component of stress granules involved in the stress response. Genes Dev. 21, 3381–3394 (2007). Describes the discovery of an unexpected link between HDAC6 and the formation of stress granules.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Gao, Y. S. et al. Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis. Mol. Cell. Biol. 27, 8637–8647 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Arnold, M. A. et al. MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev. Cell 12, 377–389 (2007).

    CAS  PubMed  Google Scholar 

  115. Zhu, P. et al. Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5, 455–463 (2004).

    CAS  PubMed  Google Scholar 

  116. Ropero, S. et al. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nature Genet. 38, 566–569 (2006).

    CAS  PubMed  Google Scholar 

  117. Bolden, J. E., Peart, M. J. & Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nature Rev. Drug Discov. 5, 769–784 (2006).

    CAS  Google Scholar 

  118. Minetti, G. C. et al. Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nature Med. 12, 1147–1150 (2006).

    CAS  PubMed  Google Scholar 

  119. Avila, A. M. et al. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J. Clin. Invest. 117, 659–671 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Tao, R. et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nature Med. 13, 1299–1307 (2007).

    CAS  PubMed  Google Scholar 

  121. Foglietti, C. et al. Dissecting the biological functions of Drosophila histone deacetylases by RNA interference and transcriptional profiling. J. Biol. Chem. 281, 17968–17976 (2006).

    CAS  PubMed  Google Scholar 

  122. Senese, S. et al. Role for histone deacetylase 1 in human tumor cell proliferation. Mol. Cell. Biol. 27, 4784–4795 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Iwabata, H., Yoshida, M. & Komatsu, Y. Proteomic analysis of organ-specific post-translational lysine-acetylation and -methylation in mice by use of anti-acetyllysine and -methyllysine mouse monoclonal antibodies. Proteomics 5, 4653–4664 (2005).

    CAS  PubMed  Google Scholar 

  124. Kim, S. C. et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell 23, 607–618 (2006).

    CAS  PubMed  Google Scholar 

  125. Xie, H., Bandhakavi, S., Roe, M. R. & Griffin, T. J. Preparative peptide isoelectric focusing as a tool for improving the identification of lysine-acetylated peptides from complex mixtures. J. Proteome Res. 6, 2019–2026 (2007).

    CAS  PubMed  Google Scholar 

  126. Jiang, T., Zhou, X., Taghizadeh, K., Dong, M. & Dedon, P. C. N-formylation of lysine in histone proteins as a secondary modification arising from oxidative DNA damage. Proc. Natl Acad. Sci. USA 104, 60–65 (2007).

    CAS  PubMed  Google Scholar 

  127. Chen, Y. et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol. Cell. Proteomics 6, 812–819 (2007).

    CAS  PubMed  Google Scholar 

  128. Garrity, J., Gardner, J. G., Hawse, W., Wolberger, C. & Escalante-Semerena, J. C. N-lysine propionylation controls the activity of propionyl-CoA synthetase. J. Biol. Chem. 282, 30239–30245 (2007).

    CAS  PubMed  Google Scholar 

  129. Mukherjee, S., Hao, Y. H. & Orth, K. A newly discovered post-translational modification — the acetylation of serine and threonine residues. Trends Biochem. Sci. 32, 210–216 (2007).

    CAS  PubMed  Google Scholar 

  130. Yang, X. J. & Grégoire, S. Metabolism, cytoskeleton and cellular signaling in the grip of protein Nε- and O-acetylation. EMBO Rep. 8, 556–561 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Mattagajasingh, I. et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl Acad. Sci. USA 104, 14855–14860 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Tang, X. et al. Acetylation-dependent signal transduction for type I interferon receptor. Cell 31, 93–105 (2007).

    Google Scholar 

  133. Lambard, D. B. et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 27, 8807–8814 (2007).

    Google Scholar 

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

    CAS  Google Scholar 

  135. Starai, V. J., Celic, I., Cole, R. N., Boeke, J. D. & Escalante-Semerena, J. C. Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine. Science 298, 2390–2392 (2002).

    CAS  PubMed  Google Scholar 

  136. Gardner, J. G., Grundy, F. J., Henkin, T. M. & Escalante-Semerena, J. C. Control of acetyl-coenzyme A synthetase (AcsA) activity by acetylation/deacetylation without NAD+ involvement in Bacillus subtilis. J. Bacteriol. 188, 5460–5468 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Hallows, W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl Acad. Sci. USA 103, 10230–10235 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Schwer, B., Bunkenborg, J., Verdin, R. O., Andersen, J. S. & Verdin, E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl Acad. Sci. USA 103, 10224–10229 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Yang, X. J. & Grégoire, S. A recurrent phospho-sumoyl switch in transcriptional repression and beyond. Mol. Cell 23, 779–786 (2006).

    PubMed  Google Scholar 

  140. Lagger, G. et al. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 21, 2672–2681 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Montgomery, R. L. et al. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 21, 1790–1802 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Zimmermann, S. et al. Reduced body size and decreased intestinal tumor rates in HDAC2-mutant mice. Cancer Res. 67, 9047–9054 (2007).

    CAS  PubMed  Google Scholar 

  143. Dannenberg, J. H. et al. mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival. Genes Dev. 19, 1581–1595 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Cowley, S. M. et al. The mSin3A chromatin-modifying complex is essential for embryogenesis and T-cell development. Mol. Cell. Biol. 25, 6990–7004 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. David, G., Turner, G. M., Yao, Y., Protopopov, A. & DePinho, R. A. mSin3-associated protein, mSds3, is essential for pericentric heterochromatin formation and chromosome segregation in mammalian cells. Genes Dev. 17, 2396–2405 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Williams, C. J. et al. The chromatin remodeler Mi-2β is required for CD4 expression and T cell development. Immunity 20, 719–733 (2004).

    CAS  PubMed  Google Scholar 

  147. Kaji, K. et al. The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nature Cell Biol. 8, 285–292 (2006).

    CAS  PubMed  Google Scholar 

  148. Marino, S. & Nusse, R. Mutants in the mouse NuRD/Mi2 component P66α are embryonic lethal. PLoS ONE 2, e519 (2007).

    PubMed  PubMed Central  Google Scholar 

  149. Wang, J. et al. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 446, 882–887 (2007).

    CAS  PubMed  Google Scholar 

  150. Hermanson, O., Jepsen, K. & Rosenfeld, M. G. N-CoR controls differentiation of neural stem cells into astrocytes. Nature 419, 934–939 (2002).

    CAS  PubMed  Google Scholar 

  151. Vega, R. B. et al. Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119, 555–566 (2004).

    CAS  PubMed  Google Scholar 

  152. Chang, S. et al. Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol. Cell. Biol. 24, 8467–8476 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Chang, S. et al. Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Cell 126, 321–334 (2006). References 151 and 153 report the unexpected phenotypes of Hdac4 - and Hdac7 -null mice, thereby revealing the essential roles of these deacetylases in bone development and maintenance of vascular integrity, respectively.

    CAS  PubMed  Google Scholar 

  154. Zhang, C. L. et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Owing to strict space constraints and the wealth of literature, we have used seminal reviews and supplemental figures and tables to cover some of the primary findings in this field. Research in our laboratories has been supported by grants from the National Institutes of Health, the American Heart Association and the Kaul Foundation (to E.S.), and from the Canadian Institutes of Health Research, the National Cancer Institute of Canada, the Natural Sciences and Engineering Research Council of Canada and the Canada Foundation for Innovation (to X.J.Y.).

Author information

Authors and Affiliations

Authors

Supplementary information

Supplementary information S1 (figure)

Domain organization of classical HDACs from Caenorhabditis elegans, Drosophila melanogaster and Danio rerio. (PDF 136 kb)

Supplementary information S2 (figure)

Sequence comparison of selective human HDACs with orthologues in sea urchin and zebrafish. (PDF 232 kb)

Supplementary information S3 (figure)

Crystal structures of the deacetylase domains of HDAC7 and HDAC8. (PDF 288 kb)

Supplementary information S4 (table)

Purification of class I and II HDAC complexes from yeast (PDF 170 kb)

Supplementary information S5 (table)

Purification of class I HDAC complexes from Xenopus laevis and mammals (PDF 249 kb)

Supplementary information S6 (table)

Roles of classical HDACs and associated subunits in worm and fly development (PDF 261 kb)

Related links

Related links

DATABASES

Entrez Protein

Hda1

HDA2

HDAC1

HDAC2

HDAC3

HDAC4

HDAC5

HDAC6

HDAC7

HDAC8

HDAC9

HDAC10

HDAC11

Rpd3

Entrez Nucleotide (GenBank)

XP_001101619

XP_001493915

OMIM

Huntington's disease

Parkinson's disease

RCSB Protein Data Bank

2NVR

FURTHER INFORMATION

Xiang-Jiao Yang's homepage

Edward Seto's homepage

SUPPLEMENTARY INFORMATION

See online article

S1 (figure)

S2 (figure)

S3 (figure)

S4 (table)

S5 (table)

S6 (table)

Glossary

Orthologue

A functionally related gene in two or more species that has evolved from a common ancestor.

Nucleosome

The basic structural subunit of chromatin, which consists of 200 base pairs of DNA wrapped around an octamer of histones.

Homologue

A gene (or its product) that is descended from a common ancestral gene.

Bromodomain

A conserved protein module that was first described for the Drosophila melanogaster homeotic gene regulator Brahma (means 'creator' in Hindu). This domain is present in many gene and/or chromatin regulators and has the ability to recognize acetyl-Lys motifs.

Deuterostome

An animal in which the anus develops from the first opening of the embryo, with the mouth being formed later. These include echinoderms and chordates.

Myocyte enhancer factor-2

(MEF2). An evolutionarily conserved transcription factor, the specific DNA-binding activity of which is mediated by an N-terminal MADS box and an adjacent MEF2-specific domain. Although initially identified as a muscle-specific transcription factor, different MEF2 isoforms are important in various tissues.

14-3-3 protein

One of a family of acidic proteins that are conserved from yeast and plants to humans and are highly abundant. They are 30 kDa in size and often recognize target proteins with the sequence motif RXXpS/TXP or RXXXpS/TXP, where X is any residue and pS/T denotes phosphoSer or phosphoThr.

ZnF-UBP

A ubiquitin-binding zinc finger that is present in HDAC6 and several ubiquitin-specific proteases.

SE14 repeat

Ser-Glu-containing tetradecapeptide repeat that is found in HDAC6 proteins from certain higher mammals.

SANT domain

A 60-residue module that was initially identified in Swi3, Ada2, N-CoR and TFIIIB as a putative DNA-binding domain. It is present in various transcriptional and chromatin regulators and is now considered to be a histone-binding module.

Chromodomain

Originally identified as a 37-amino-acid-residue chromobox shared by the heterochromatin protein HP1 and the polycomb protein Pc2, it has subsequently been found in many other chromatin regulators and recognizes methyl-Lys protein motifs.

Mating-type gene

One of a number of genes in the yeast chromosome that control the sexual fate of the yeast cell.

PHD finger

A plant homeodomain-linked (PHD) zinc finger that chelates double zinc ions. This type of zinc finger is present in many chromatin regulators and was recently shown to bind the N-terminal tails of core histones in a methylation-dependent or -independent manner.

Euchromatic

DNA that contains most of the structural genes. It changes structure during the cell cycle and undergoes transcriptional regulation.

Chaperone

A protein that mediates the assembly of another polypeptide-containing structure, but does not form part of the completed structure or participate in its biological function.

Paralogue

A sequence, or gene, that has originated from a common ancestral sequence, or gene, by a duplication event.

microRNA

A small RNA of 21 nucleotides that regulates the expression of mRNAs to which it is complementary in sequence.

Microtubule

A hollow tube, 25 nm in diameter, that is formed by the lateral association of 13 protofilaments, which are themselves polymers of α- and β-tubulin subunits.

Chemotaxis

A type of migration that is stimulated by a gradient of a chemical stimulant or chemoattractant.

Immune synapse

A junction that forms at the contact region between a T cell and its target cells. T-cell activation occurs here.

F-actin

(Filamentous actin). A flexible, helical polymer of G-actin (globular actin) monomers that is 5–9 nm in diameter.

AAA+ family of ATPases

A superfamily of ATPases that are associated with various cellular activities. They have one or two nucleotide-binding domains ('AAA modules'), which often form ring-like oligomers and function as chaperones in diverse cellular processes.

Inclusion body

An insoluble aggregate of misfolded proteins. Inclusion bodies are common in prokaryotes and in the brains of patients with triplet-repeat diseases.

Dynein

A microtubule-based molecular motor that moves towards the minus end of microtubules.

Kinesin

A microtubule-based molecular motor that is most often directed towards the plus end of microtubules.

Autophagy

A pathway for the recycling of cellular contents, in which materials inside the cell are packaged into vesicles and then targeted to the vacuole or lysosome for bulk turnover.

Macropinocytosis

A form of regulated endocytosis that involves the formation of large endocytic vesicles after the closure of cell-surface membrane ruffles.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, XJ., Seto, E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 9, 206–218 (2008). https://doi.org/10.1038/nrm2346

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2346

This article is cited by

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