Precise deposition of histone H2A.Z in chromatin for genome expression and maintenance

doi:10.1016/j.bbagrm.2011.10.004

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

Volume 1819, Issues 3–4, March–April 2012, Pages 290-302

https://doi.org/10.1016/j.bbagrm.2011.10.004 Get rights and content

Abstract

Histone variant H2A.Z is essential in higher eukaryotes and has different functions in the cell. Several studies indicate that H2A.Z is found at specific loci in the genome such as regulatory-gene regions, where it poises genes for transcription. Its deposition creates chromatin regions with particular structural characteristics which could favor rapid transcription activation. This review focuses on the highly regulated mechanism of H2A.Z deposition in chromatin which is essential for genome integrity. Chaperones escort H2A.Z to large ATP-dependent chromatin remodeling enzymes which are responsible for its deposition/eviction. Over the last ten years, biochemical, genetic and genomic studies helped us understand the precise role of these complexes in this process. It has been suggested that a cooperation occurs between histone acetyltransferase and chromatin remodeling activities to incorporate H2A.Z in chromatin. Its regulated deposition near centromeres and telomeres also shows its implication in chromosomal structure integrity and parallels a role in DNA damage response. The dynamics of H2A.Z deposition/eviction at specific loci was shown to be critical for genome expression and maintenance, thus cell fate. Altogether, recent findings reassert the importance of the regulated deposition of this histone variant. This article is part of a Special Issue entitled: Histone chaperones and Chromatin assembly.

Highlights

► Histone variant H2A.Z is implicated in genome expression and maintenance. ► H2A.Z has a very distinct mechanism of deposition/eviction on chromatin. ► Chromatin modifications regulate H2A.Z incorporation.

Introduction

To maintain stability and integrity of the genome, eukaryotic DNA is organized in a highly regulated structure called chromatin. DNA molecules are bound by highly conserved proteins providing structural support to control important functions of the genome. Chromatin is a repetition of nucleosomes formed by 146 bp of DNA wrapped around an octamer of proteins composed of two copies of each canonical histone H3, H4, H2A and H2B [1]. The chromatin assembly model implies two steps. First, a core (H3/H4)2 tetramer is assembled, and then, two H2A/H2B dimers associate separately with the tetramer to form the histone octamer [2]. Histones are small basic proteins that contain a core globular domain and a positively charged flexible N-terminal tail. Several amino acids on the tails can be modified by posttranslational modifications and different combinations of these have been proposed to form an epigenetic code [3]. These signatures direct gene expression and the function of regulatory sequences like promoters or replication origins, thereby progression through the cell cycle [4].

The reconfiguration of local chromatin creates specialized domains. Accessibility of regulatory elements is facilitated by four processes that change chromatin structure. First, ATP-dependent chromatin remodeling complexes are able to slide, disrupt or remove nucleosomes [5]. Second, N-terminal tails of histones can be modified by addition of covalent modification(s) such as acetylation, methylation, ubiquitination, sumoylation and/or phosphorylation [6]. Third, histone chaperones participate in the regulated assembly and disassembly of nucleosomes during most DNA transactions [7]. Finally, the incorporation of non-canonical histone variants within nucleosomes leads to specialized chromatin domains [8]. Some histones have variants that differ in amino acid sequence from the canonical one and can be exchanged in the same nucleosome at specific locations in the genome. Specific incorporation of variants can be performed by specific ATP-dependent remodeling complexes and/or specialized histone chaperone [8], [9], [10].

Section snippets

Histone H2A.Z

Histone H2A has the largest number of variants with specific and highly conserved functions. Particular H2A variants like H2A.Z or H2A.X have important functions for cell proliferation and viability and are implicated in different processes [11]. The phylogenetic studies of histone variant H2A.Z showed an early divergence in evolution between species, acquiring specialized functions [12]. H2A.Z genes are essential for development and viability in many organisms. Disruption of H2A.Z genes leads

H2A.Z-specialized local chromatin structure

Histone variants differ from the canonical ones in their primary sequences and by specific nucleosome properties within chromatin [38]. The addition of variants can change the physiochemical properties of the nucleosome (Fig. 1A). As a consequence both the stable interaction between DNA and nucleosome as well as the accessibility of the DNA can be altered [39]. H2A.Z variants share about 90% similarity among the various higher eukaryotes. H2A and H2A.Z differ in amino acid sequence but share

Deposition is assisted by specific histone chaperones

It is now believed that the majority of H2A.Z incorporation into chromatin is performed by Swr1-related ATP-dependent chromatin remodelers that specifically exchange canonical H2A–H2B for H2A.Z–H2B dimers within nucleosomes [58] (discussed in section below). It is also believed that specific chaperones are able to provide H2A.Z–H2B dimers to the exchange reaction or during chromatin assembly. Histone chaperones are known important modulators of chromatin organization [7]. Various chaperones

Deposition occurs at specific locations in the genome

The focus of this review is the mechanism of H2A.Z deposition/eviction in chromatin, but to understand how deposition occurs we need to understand where it happens. Because the canonical histone octamer occurs approximately every 200 bp over billions of DNA base pairs in the genome, non-random H2A.Z deposition on chromatin must be very specific and highly regulated.

Different genome-wide chomatin immunoprecipitation (ChIP) studies in several organisms precisely mapped H2A.Z along chromosomes. In

Roles at multiple steps of transcription

The transcriptional role of H2A.Z was first observed by Allis and colleagues who found this variant in the transcriptionally active macronucleus of Tetrahymena thermophila [72]. Since then, contradicting data have been found in different organisms suggesting a positive or a negative role in transcription. In yeast, the non-lethal ∆htz1 strain showed a defect in the activation of inducible genes confirming a positive role in transcription [21], [35], [71], [73]. It was shown that H2A.Z has

Important roles for H2A.Z to maintain genome integrity

The fact that the deletion of the H2A.Z gene is lethal in most eukaryotes may be indicative of its many roles in the cell. Currently, its various functions in transcription are most well characterized. However, thanks to loss of function studies, it has been proposed that H2A.Z variants play roles in other cell processes important for genome maintenance and integrity [84].

H2A.Z is implicated in chromosome integrity through functional interactions with factors required for proper chromosome

Conserved chromatin-remodeling complexes act in H2A.Z deposition/eviction

All these different roles of H2A.Z variant implicate recruitment mechanisms for deposition at specific loci. Incorporation in chromatin implies different steps. To replace canonical dimers by variant dimers, SWR1-related complexes evict them from the nucleosome and replace them by H2A.Z-containing dimers. But the opposite is also required in order to reset the nucleosome, i.e. H2A.Z needs to be removed and exchanged for canonical histone H2A. It has been proposed that this process of

Work shared by all subunits

Yeast SWR1 complex is a large complex of numerous subunits, each containing specific domain(s) which contribute to the overall structure of the complex or directly to the deposition activity. The recruitment of the complex to promoters is directly dependent on the protein/domain composition of SWR1 and is typically enriched to the same degree as H2A.Z [105], [125]. Biochemical studies helped to characterize the role of each subunit. H2A.Z binds the SWR1 complex at two different locations on the

Post-translational modifications implicated in deposition

Post-translational modifications of histone tails are involved in the alteration of higher-order folding of chromatin and in the creation of binding sites for non-histone proteins [136]. Acetylation of lysine residues by acetyltransferases represents a major post-translational modification which occurs in the cell on either histones or non-histone proteins [137].

The N-terminal tail of H2A.Z is acetylated in different species [68], [138], [139], [140], [141]. Human H2A.Z is precisely acetylated

Eviction to maintain genome integrity

Maintaining stability and integrity of the genome is essential for cell survival. As such, genomic instability is a common hallmark of many human cancers [152]. The regulation of chromatin structure is an important player in the maintenance of genome integrity. As we have already discussed in this review, H2A.Z has diverse important roles such as transcription, chromatin boundaries and at certain regulatory elements. As a result, expression itself has to be highly controlled because

Perspectives

H2A.Z is closely linked to genome integrity and cancer. In fact, problems in H2A.Z expression level are found in cancer cell lines where its overexpression is linked to disease progression [153], [159], [160], [161]. Moreover, altered H2A.Z functions lead to tumorigenesis notably for progression to the metastatic stage and now represent a possible new target for cancer therapies [156], [162]. In addition, this could be linked to its mislocalization due to an abnormal deposition leading to

Acknowledgments

We apologize to our colleagues for work that could not be cited due to space limitation. We are grateful to Marie-Eve Lalonde for her help and Rhea Utley for text editing. Work in our laboratory is supported by operating grants from the Canadian Institutes of Health Research (CIHR, MOP-14308/64289). J.C. holds a Canada Research Chair.

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^☆: This article is part of a Special Issue entitled: Histone chaperones and Chromatin assembly.

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ReviewPrecise deposition of histone H2A.Z in chromatin for genome expression and maintenance☆

Abstract

Highlights

Introduction

Section snippets

Histone H2A.Z

H2A.Z-specialized local chromatin structure

Deposition is assisted by specific histone chaperones

Deposition occurs at specific locations in the genome

Roles at multiple steps of transcription

Important roles for H2A.Z to maintain genome integrity

Conserved chromatin-remodeling complexes act in H2A.Z deposition/eviction

Work shared by all subunits

Post-translational modifications implicated in deposition

Eviction to maintain genome integrity

Perspectives

Acknowledgments

Cell

Mol. Cell

Curr. Opin. Genet. Dev.

J. Biol. Chem.

Curr. Biol.

Cell

Cell

Cell

Cell

Cell

Mol. Cell

Cell

Cell

Structure

Trends Biochem. Sci.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

Cell

Mol. Cell

Cell

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Curr. Opin. Cell Biol.

Mol. Cell

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Crystal structure of the nucleosome core particle at 2.8 A resolution

Nature

Histone structure and the organization of the nucleosome

Annu. Rev. Biophys. Biomol. Struct.

The language of covalent histone modifications

Nature

Translating the histone code

Science

The biology of chromatin remodeling complexes

Annu. Rev. Biochem.

Histone variants—ancient wrap artists of the epigenome

Nat. Rev. Mol. Cell Biol.

Connection between histone H2A variants and chromatin remodeling complexes

Biochem. Cell Biol.

Reuniting the contrasting functions of H2A.Z

Biochem. Cell Biol.

Phylogenetic analysis of the core histones H2A, H2B, H3, and H4

Nucleic Acids Res.

Essential and nonessential histone H2A variants in Tetrahymena thermophila

Mol. Cell. Biol.

H2A.ZI, a new variant histone expressed during Xenopus early development exhibits several distinct features from the core histone H2A

Nucleic Acids Res.

Drosophila has a single copy of the gene encoding a highly conserved histone H2A variant of the H2A.F/Z type

Nucleic Acids Res.

Regions of variant histone His2AvD required for Drosophila development

Nature

Changes in the nuclear deposition of histone H2A variants during pre-implantation development in mice

Development

H2A.Z is required for global chromatin integrity and for recruitment of RNA polymerase II under specific conditions

Mol. Cell. Biol.

Acetylation of H2AZ Lys 14 is associated with genome-wide gene activity in yeast

Genes Dev.

Variant histone H2A.Z is globally localized to the promoters of inactive yeast genes and regulates nucleosome positioning

PLoS Biol.

Review
Precise deposition of histone H2A.Z in chromatin for genome expression and maintenance☆