Trends in Genetics
Volume 19, Issue 5, May 2003, Pages 286-293
Journal home page for Trends in Genetics

Class II histone deacetylases: versatile regulators

https://doi.org/10.1016/S0168-9525(03)00073-8Get rights and content

Abstract

Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes. Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues in the histone N-terminal tails and are found in large multiprotein complexes with transcriptional co-repressors. Human HDACs are grouped into three classes based on their similarity to known yeast factors: class I HDACs are similar to the yeast transcriptional repressor yRPD3, class II HDACs to yHDA1 and class III HDACs to ySIR2. In this review, we focus on the biology of class II HDACs. These newly discovered enzymes have been implicated as global regulators of gene expression during cell differentiation and development. We discuss their emerging biological functions and the molecular mechanisms by which they are regulated.

Section snippets

The class IIa HDACs: HDAC4, -5, -7 and -9

HDAC4, -5, -7 and -9 contain a highly conserved C-terminal catalytic domain (∼420 amino acids) homologous to yHDA1 and an N-terminal domain with no similarity to other proteins (Fig. 1b) 4, 5, 6, 7, 13. MITR, a splice variant of HDAC9, consists of only its N-terminus without an HDAC domain. The activity of the class IIa HDACs is regulated at several levels, including tissue-specific gene expression, recruitment of distinct cofactors and nucleocytoplasmic shuttling.

The class IIb HDACs: HDAC6 and HDAC10

Class IIb HDACs are characterized by duplicated HDAC domains, although this duplication is partial in the case of HDAC10 (Fig. 1b). Class IIb HDACs also show some degree of tissue-specific gene expression: HDAC6 is predominantly expressed in testis 13, 83, and HDAC10 is expressed in liver, spleen and kidney 8, 10, 12. Different splice variants are observed for HDAC10, as shown for HDAC3, -7 and -9, suggesting an additional level of regulation by RNA processing. Analysis of the catalytic

Future questions

The purification, cloning and characterization of class II HDACs have provided important insights into how chromatin controls transcription and have revealed unexpected biological functions for acetylation. The past two years have seen the elucidation of discrete biological pathways in which class II HDACs play crucial regulatory roles. Whereas class IIa HDACs are frequently considered functionally redundant, it is likely that further study will reveal discrete biological functions specific for

Acknowledgements

We thank John Carroll and Jack Hull for graphics, and Stephen Ordway and Gary Howard for editorial assistance. We thank colleagues for sharing unpublished observations and apologize to those whose work could not be cited due to space constraints. Our work is supported by the NIH, The Sandler Foundation and the J. David Gladstone Institutes.

References (90)

  • C.L. Zhang

    Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor

    J. Biol. Chem.

    (2001)
  • H.Y. Kao

    Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7

    J. Biol. Chem.

    (2001)
  • H.-D. Youn

    Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4

    J. Biol. Chem.

    (2000)
  • C.W. Wong

    Components of the SMRT co-repressor complex exhibit distinctive interactions with the POZ domain oncoproteins PLZF, PLZF-RARα, and BCL-6

    J. Biol. Chem.

    (1998)
  • A.L. Shaffer

    BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control

    Immunity

    (2000)
  • C. Lemercier

    Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor

    J. Biol. Chem.

    (2002)
  • G. David

    SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities

    J. Biol. Chem.

    (2002)
  • U. Dressel

    A dynamic role for HDAC7 in MEF2-mediated muscle differentiation

    J. Biol. Chem.

    (2001)
  • X. Zhao

    The modular nature of histone deacetylase HDAC4 confers phosphorylation-dependent intracellular trafficking

    J. Biol. Chem.

    (2001)
  • A.J. Muslin

    14-3-3 proteins: regulation of subcellular localization by molecular interference

    Cell. Signal.

    (2000)
  • C.L. Zhang

    Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy

    Cell

    (2002)
  • J. Lu

    Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases

    Mol. Cell

    (2000)
  • W. Fischle

    Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR

    Mol. Cell

    (2002)
  • J. Zhang

    The N-CoR-HDAC3 nuclear receptor co-repressor complex inhibits the JNK pathway through the integral subunit GPS2

    Mol. Cell

    (2002)
  • B.J. North

    The human Sir2 ortholog, hSIRT2, is an NAD+-dependent tubulin deacetylase

    Mol. Cell

    (2003)
  • T.A. McKinsey

    MEF2: a calcium-dependent regulator of cell division, differentiation and death

    Trends Biochem. Sci.

    (2002)
  • Z. Mao

    Calcineurin enhances MEF2 DNA binding activity in calcium-dependent survival of cerebellar granule neurons

    J. Biol. Chem.

    (1999)
  • T.A. McKinsey

    Control of muscle development by dueling HATs and HDACs

    Curr. Opin. Genet. Dev.

    (2001)
  • C. Lemercier

    mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity

    J. Biol. Chem.

    (2000)
  • J. Milbrandt

    Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene

    Neuron

    (1988)
  • F. Blaeser

    Ca(2+)-dependent gene expression mediated by MEF2 transcription factors

    J. Biol. Chem.

    (2000)
  • H.D. Youn

    Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2

    Immunity

    (2000)
  • A. Verdel

    Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm

    Curr. Biol.

    (2000)
  • D. Robyr

    Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases

    Cell

    (2002)
  • W. Fischle

    The emerging role of class II histone deacetylases

    Biochem. Cell Biol.

    (2001)
  • C.M. Grozinger

    Three proteins define a class of human histone deacetylases related to yeast Hda1p

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • E.A. Miska

    HDAC4 deacetylase associates with and represses the MEF2 transcription factor

    EMBO J.

    (1999)
  • A.H. Wang

    HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional co-repressor

    Mol. Cell. Biol.

    (1999)
  • J.J. Tong

    Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain

    Nucleic Acids Res.

    (2002)
  • X. Zhou

    Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • X. Zhou

    Cloning and characterization of a histone deacetylase, HDAC9

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • H.Y. Kao

    Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression

    Genes Dev.

    (2000)
  • C.M. Grozinger

    Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • A.H. Wang

    Regulation of histone deacetylase 4 by binding of 14-3-3 proteins

    Mol. Cell. Biol.

    (2000)
  • T.A. McKinsey

    Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • Cited by (563)

    • Various epigenetic regulators

      2023, Transcription and Translation in Health and Disease
    View all citing articles on Scopus
    View full text