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The many roles of histone deacetylases in development and physiology: implications for disease and therapy

Nature Reviews Genetics volume 10, pages 32–42 (2009)Cite this article

Key Points

  • Mammalian genomes encode eleven proteins of the classical histone deacetylase (HDAC) family. They are numbered HDAC1 to HDAC11 and can be classified into four distinct groups (class I, IIa, IIb and IV), which differ in structure, enzymatic function, subcellular localization and expression patterns.

  • Class I HDACs (HDAC1, 2, 3 and 8) are ubiquitously expressed highly active enzymes which localize predominantly to the nucleus. Genetic deletion is lethal in all cases with phenotypes ranging from gastrulation defects to cardiovascular malformation.

  • Class IIa HDACs (HDAC4, 5, 7 and 9) are signal-responsive transcriptional repressors that interact with the transcription factor myocyte enhancer factor 2 (MEF2) and have minimal enzymatic activity towards classical histone substrates, owing to a conserved amino-acid change in the catalytic pocket. Genetic deletion leads to superactivation of MEF2 with resulting phenotypes in the heart, skeleton and endothelial cells.

  • HDAC6 and HDAC10 form the class IIb HDAC family, with HDAC6 being the main cytoplasmic deacetylase in mammalian cells. HDAC6 has numerous targets, including tubulin and intracellular chaperones. Genetic deletion of HDAC6 does not lead to an overt phenotype.

  • HDAC11 is the sole member of the class IV HDACs. Little is known about its function.

  • Genetic deletion of individual HDACs leads to surprisingly specific phenotypes. Analysis of the resulting mutants has shown that HDACs control specific gene expression programmes.

  • One major challenge for the future will be to decipher the role of individual HDACs in specific disease processes and to develop isoform-specific inhibitors. It is expected that this will lead to a broader therapeutic window of HDAC inhibitors, and possibly to a clinical application in non-oncological disease states.

Abstract

Histone deacetylases (HDACs) are part of a vast family of enzymes that have crucial roles in numerous biological processes, largely through their repressive influence on transcription. The expression of many HDAC isoforms in eukaryotic cells raises questions about their possible specificity or redundancy, and whether they control global or specific programmes of gene expression. Recent analyses of HDAC knockout mice have revealed highly specific functions of individual HDACs in development and disease. Mutant mice lacking individual HDACs are a powerful tool for defining the functions of HDACs in vivo and the molecular targets of HDAC inhibitors in disease.

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Figure 1: The histone deacetylase (HDAC) superfamily, showing protein domains, loss-of-function phenotypes in mice and time point of lethality of the knockouts.
Figure 2: Control of heart development by histone deacetylase 1 (HDAC1) and HDAC2.
Figure 3: Control of chondrocyte hypertrophy by histone deacetylase 4 (HDAC4).
Figure 4: Control of pathological cardiac hypertrophy by class IIa histone deacetylases (HDACs).
Figure 5: Control of slow myofibre gene expression by class IIa histone deacetylases (HDACs).
Figure 6: Control of endothelial integrity by histone deacetylase 7 (HDAC7).

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Acknowledgements

We apologize to the many authors in the field whose work we were not able to cite because of space constraints. Research in the Olson laboratory has been supported by grants from the National Institutes of Health, the D.W. Reynolds Clinical Cardiovascular Research Center, the Robert A. Welch Foundation and the Sandler Foundation for Asthma Research. M.H was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG, HA 3335/2-1).

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  1. Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, 75390-9148, Texas, USA

    Michael Haberland, Rusty L. Montgomery & Eric N. Olson

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  1. Michael Haberland
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  2. Rusty L. Montgomery
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  3. Eric N. Olson
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Correspondence to Eric N. Olson.

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Eric Olson is a consultant for Gilead Therapeutics.

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http://www4.utsouthwestern.edu/olsonlab

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Haberland, M., Montgomery, R. & Olson, E. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10, 32–42 (2009). https://doi.org/10.1038/nrg2485

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