Review
Functional significance of histone deacetylase diversity

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Abstract

Nucleocytoplasmic shuttling of histone deacetylases is emerging as a major step in determining the composition, and hence the activity, of the corresponding nuclear regulatory complexes. This shuttling process is one of the distinctive characteristics of these enzymes, themselves belonging to structurally and functionally different classes. Considering the specific features of each class of deacetylases, it is possible to determine how each member can contribute to particular cellular functions.

Introduction

Specific lysines present in the tail of core histones, as well as in other cellular and viral proteins, are sites of reversible acetylation. In the case of histones, this post-translational modification appears to constitute a signal [1] that may function in combination with other covalent modifications to generate an epigenetic code. This information is, in turn, interpreted in terms of modified states of chromatin structure and function 2., 3., 4.. This specific signal is reversed by machinery containing an essential group of enzymes, known as histone deacetylases (HDACs). The understanding of the nature and function of this machinery relies on the identification of the catalytic subunits, as well as on that of the partner proteins. In different species, an increasing number of HDACs are being identified [5], implying that they might be involved in specialized functions. The identification of the first HDAC [6] revealed the existence of a family of proteins in higher eukaryotes related to a known yeast protein, RPD3 [7]. These proteins exhibit a similar domain organization [8] and could be grouped in a class, now known as class I HDACs. As other HDACs, distinct from RPD3, were found in yeast [9], an analogous situation was expected in higher eukaryotes. A search for other HDACs resulted in the discovery of a second class of HDACs related to yeast HDA1, first in mouse [10], and then in human 11., 12.. Interestingly, another yeast protein, SIR2, was shown recently to be a HDAC and its mammalian homologues have also been identified as HDACs 13, 14., 15.. Therefore, SIR2-related proteins could form a third class of HDACs in higher eukaryotes. The diversity of histone deacetylases has also been observed in plants; indeed, classes other than the well conserved RPD3-related class I HDACs have been characterized, containing enzymes unrelated to RPD3 [16]. The diversity of HDACs strongly suggests that members of each class may be involved in distinct, and perhaps overlapping, functions. The aim of our review is to evaluate how the diversity of HDACs could be linked to distinct functions in the animal kingdom.

Section snippets

Functional diversity in the class I histone deacetylases

To date, four enzymes, HDAC1, 2, 3 and 8 5., 17., are the known members of the class I deacetylases, including different splice variants of HDAC3 [18]. Members of this class contain a well-conserved catalytic domain that in HDAC1, 2 and 3 encompasses almost two thirds of the protein. The remaining carboxy-terminal portion contains the most divergent sequences and is a distinguishing feature among these different members [8]. HDAC1 and HDAC2 were identified as components of two multiprotein

Functional diversity in the class II histone deacetylases: linkage between their nucleocytoplasmic shuttling and their functions

The class II HDACs, comprising HDACs 4–7, were identified on the basis of their catalytic domain homology to yeast HDA1 protein. They possess several features that distinguish them from the class I members: they are larger (almost twice the size) and the catalytic domain of HDAC4, 5 and 7 is located in the carboxy-terminal half of the protein (Fig. 1). HDAC6 is a unique deacetylase, possessing two catalytic domains 10., 12. and is probably a functionally distinct member of the family [28radical dot]. Some

Class III histone deacetylases: enzymes linking cell metabolism to the control of histone acetylation

SIR2, a yeast repressor of transcription has been shown recently to have an in vitro NAD+-dependent HDAC activity 13, 14., 15.. Here again, as with yeast RPD3 and HDA1 [8], a large domain of the protein shows significant sequence homology with a group of prokaryotic enzymes 37., 38.. Yeast SIR2 can be considered, therefore, as a founding member of a large family of related proteins present in higher eukaryotes that we will refer to here as class III HDACs. A detailed analysis of all the

Conclusions

Different members of class I and/or class II HDACs are found together in various nuclear complexes. Unfortunately, up to now there has been no hint regarding the significance of the participation of multiple HDACs in one regulatory complex. One might expect, however, the activity of a specific complex to be dependent on the presence of a particular combination of HDACs. Accordingly, the regulation of the intracellular localization of all the class II HDACs through a controlled nucleocytoplasmic

Update

Endogenous HDAC5 present in the nucleus of C2 myoblasts is efficiently exported into the cytoplasm upon their differentiation into myotubes. The phosphorylation of HDAC5 by the calcium/calmodulin-dependent protein kinase, CaMK, is found to play an essential role in the nuclear export of HDAC4 and 5 and therefore in the control of myogenesis [45]. Moreover, this CaMK-dependent phosphorylation of HDAC5 enhances its binding to 14-3-3 and its retention in the cytoplasm [46]. In contrast, the

Acknowledgements

We are grateful to Hung-Ying Kao for communicating results prior publications and the critical reading of the manuscript. To Joseph Torchia, Xiang-Jiao Yang and Sophie Rousseaux, for the critical reading of this manuscript and helpful suggestions. D Seigneurin-Berny. is a recipient of a post-doctoral fellowship from the ‘Association pour la Recherche sur le Cancer’, A Verdel is a recipient of a PhD fellowship from the ‘Ligue Nationale Contre le Cancer, comité de la Haute Savoie’ and C Lemercier

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • radical dot of special interest

  • radical dotradical dot of outstanding interest

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