Review
Chaperoning the histone H3 family☆

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Abstract

Chromatin is a highly dynamic nucleoprotein structure, which orchestrates all nuclear process from DNA replication to DNA repair, from transcription to recombination. The proper in vivo assembly of nucleosome, the basic repeating unit of chromatin, requires the deposition of two H3–H4 dimer pairs followed by the addition of two dimers of H2A and H2B. Histone chaperones are responsible for delivery of histones to the site of chromatin assembly and histone deposition onto DNA, histone exchange and removal. Distinct factors have been found associated with different histone H3 variants, which facilitate their deposition. Unraveling the mechanism of histone deposition by specific chaperones is of key importance to epigenetic regulation. In this review, we focus on histone H3 variants and their deposition mechanisms. This article is part of a Special Issue entitled:Histone chaperones and Chromatin assembly.

Highlights

► In this review, we focus on the mechanism of histone H3 variants deposition. ► We highlight the role of histone chaperones in their incorporation to chromatin. ► We discuss how H3 variants contribute to marking specific chromosomal domains.

Introduction

The genome in eukaryotic cell is composed of DNA, histone and non-histone proteins, which are assembled into highly compact structure known as chromatin. The basic building block of chromatin, the nucleosome, contains 147 bp of DNA wrapped around an octamer of the four core histones (H2A, H2B, H3 and H4) in ~ 1.7 super helical turns. The nucleosomes are connected with linker DNA and the resulting structure is called the 10 nm chromatin filament. The 10 nm filament further compacts into the 30 nm fiber through interaction with linker histones. The higher order chromatin structures are formed upon folding of the 30 nm fibers [1]. Despite this high level of compaction, eukaryotic chromatin is highly dynamic and allows access to the DNA template during various vital cellular processes. This dynamic nature of chromatin structure is regulated by different protein factors, including histone chaperones, ATP-dependent chromatin remodeling factors, histone variants, histone post-translational modifications (acetylation, methylation and phosphorylation) [2] and still many other unknown factors.

Histone variants are non-allelic isoforms of conventional histones. All histones, except histone H4, possess histone variants. The family of H3 histones includes the conventional histones H3.1, H3.2 and the histone variants H3t, H3.3, CENP-A (Centromere Protein A), H3.X, H3.Y and H3.5 (Fig. 1).

The deposition of histones in chromatin is assisted by histone chaperones. In the context of chromatin assembly chaperones can be defined as histone binding proteins responsible for the safe delivery of histones to DNA without being part of the final reaction product. After the discovery in 1978 [3] by Laskey of nucleosoplasmin, the first chaperone, a variety of chaperones have been identified and characterized. Chaperones play a role in histone deposition on DNA in replication dependent and replication independent manner, but are also implicated in their storage, transfer, exchange and removal. Moreover, chaperones prevent the non-specific and deleterious interaction of histones with other factors and DNA. In this review, we focus on the role of histone chaperones in the supply and the deposition of histone H3 proteins on DNA.

Section snippets

Histone H3 family: conventional and variant histones

Human core histones are encoded by intronless multicopy genes, which are transcribed into non-polyadenylated mRNAs. In contrast, the variant histones are encoded by genes, which are located outside the canonical histone gene cluster. They are mostly present as single or few gene copies, contain introns and their mRNAs are polyadenylated. Histone variants are evolved from the corresponding canonical histones and differ from their canonical paralogs in primary sequence, expression timing and

Chaperoning histones H3–H4 from the cytoplasm to the nucleus

The first step in the deposition of the newly synthesized histones is the transport from the cytoplasm to the nucleus, a process, which is assisted by distinct chaperones. The chaperone Asf1 (Anti-silencing Function 1) was the first chaperone identified to play a key role in supplying histones H3–H4 to the downstream chaperones, like CAF-1 (Chromatin Assembly Factor 1) and HIRA (Histone Regulatory homolog A) for nucleosome assembly [7], [8], [9], [10]. Human Asf1 exists in two isoforms, Asf1a

Chaperoning histone H3 proteins from nucleus to chromatin

Analysis of the preassembly complexes associated with the different human H3 variants has identified CAF1, Asf1a/b, HIRA, DAXX, and HJURP as the major histone chaperones controlling their targeting and deposition to specific chromatin loci (Table 1). CAF1 is the key chaperone in replication coupled chromatin assembly, while Asf1a/b plays a role in both replication coupled and replication independent deposition. The deposition of replication independent histone H3 variant H3.3 is assisted by

Replication coupled deposition of canonical H3 histones

The canonical histones H3.1 and H3.2 are synthesized and deposited during S-phase of the cell cycle in a replication-dependent manner. During replication the “old” nucleosomes are disassembled and the “new” ones are assembled. There are two sources of histones for the replication-coupled deposition: (i) “old” histones and, (ii) newly synthesized histones. According to the generally accepted view, replication-induced disruption of “old” nucleosomes produces two H2A–H2B dimers and H3–H4 tetramer

Deposition of newly synthesized conventional H3.1 histones

As mentioned earlier CAF-1 is the bona fide chaperone for replication coupled chromatin assembly. CAF-1 was first identified in humans and was shown to promote chromatin assembly on replicating SV40 DNA in vitro[29]. In mammals, the CAF-1 complex is composed of three highly conserved subunits p150, p60 and p48 [30], [31]. The p150 subunit of CAF-1 is recruited to the site of DNA synthesis through direct interaction with proliferating cell nuclear antigen (PCNA) and colocalizes with the

Deposition of H3.1–H4 following DNA Repair

DNA repair process is coupled with disruption and restoration of chromatin structure. A well recognized model for DNA repair was suggested by Smerdon [43] called “Access-Repair-Restore”. According to this model, in order the repair machinery to get access to DNA, chromatin has to be first disrupted and reassembled after completion of DNA repair. The role of chaperones (Asf1 and CAF-1) in chromatin restoration is relatively well understood compared to the chromatin disassembly during DNA repair.

Replication independent deposition of H3.3

Unlike canonical histones the expression and deposition of H3 variants occur throughout the cell cycle. It is well documented that the synthesis of histone H3.3 takes place outside S-phase [50]. The level of H3.3 transcript is constitutively maintained throughout differentiation [51]. This constitutive expression pattern makes H3.3 variants available for deposition and replacement independent of DNA replication. Noteworthy, H3.3 exhibits differences in the primary amino acid sequence and PTMs

HIRA mediated deposition of H3.3

HIRA was the first described chaperone responsible for H3.3 deposition. Initially, DNA replication independent chromatin assembly in vitro was found to be facilitated by HIRA in Xenopus egg extracts [67] and histones were identified as proteins able to specifically interact with HIRA [68]. The subsequent affinity purification study in human cells identified two distinct chaperones, CAF-1 and HIRA, for replication dependent and replication independent assembly of H3.1 and H3.3, respectively [15]

DAXX mediated deposition of H3.3

DAXX was initially linked to FAS-mediated apoptosis [73]. DAXX was found to colocalize with both the promyelocytic leukaemia (PML) nuclear body and the alpha-thalassemia/mental retardation X-linked syndrome protein (ATRX), which is highly enriched at pericentric heterochromatin [74], [75]. Recently, our group [63] and the group of Allis [62], [76] showed that DAXX, in complex with ATRX, facilitates H3.3 deposition. DAXX directly and specifically interacts with H3.3 both in vivo and in vitro and

Mechanism of CENP-A deposition at centromeres

CENP-A synthesis and deposition at centromeres is cell cycle dependent. In human the peak of the synthesis of CENP-A occurs during G2-phase [77] and deposition of CENP-A at centromeric DNA starts late in mitosis and continues to early G1-phase [77], [78]. Noteworthy, incorporation of CENP-A into centromeric chromatin is not coupled with DNA replication [79]. This uncoupling of CENP-A deposition from replication of centromeric DNA results in “dilution” of CENP-A at centromeres of daughter

Concluding remarks

Histone chaperones play essential roles in numerous nuclear processes. This review has highlighted the progress in our knowledge on the chaperones responsible for the deposition of the histones from the H3 family. Analysis of the reported data demonstrated the fascinating operation mechanism of H3 chaperones and how very little changes in the primary sequences of H3 histones resulted in changes in their structure, which are further recognized by specific chaperones. Despite the efforts

Acknowledgments

We would like to thank Dr. Stefan DIMITROV for helpful discussions and carefully reading and commenting on this manuscript. We are also thankful to all lab members for helpful discussions especially Arnaud DEPAUX. M. Shuaib acknowledges Higher Education Commission of Pakistan and currently ARC (Association pour la Recheche sur le Cancer) for financial support. The research in our team is supported by grants from CNRS, INSERM, INCA, ANR, ARC and FRM.

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

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