Histone variants and epigenetic inheritance

Biochimica et Biophysica Acta 1819 (2012) 222–229

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Biochimica et Biophysica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a g r m

Review

Histone variants and epigenetic inheritance ☆ Gang Yuan a, b, Bing Zhu b,⁎ a b

Life Science College, Beijing Normal University, Beijing, 100875, China National Institute of Biological Sciences, Beijing, 102206, China

a r t i c l e

i n f o

Article history: Received 4 May 2011 Received in revised form 8 June 2011 Accepted 9 June 2011 Available online 17 June 2011 Keywords: Histone variant Epigenetics Chromatin

a b s t r a c t Nucleosome particles, which are composed of core histones and DNA, are the basic unit of eukaryotic chromatin. Histone modifications and histone composition determine the structure and function of the chromatin; this genome packaging, often referred to as “epigenetic information”, provides additional information beyond the underlying genomic sequence. The epigenetic information must be transmitted from mother cells to daughter cells during mitotic division to maintain the cell lineage identity and proper gene expression. However, the mechanisms responsible for mitotic epigenetic inheritance remain largely unknown. In this review, we focus on recent studies regarding histone variants and discuss the assembly pathways that may contribute to epigenetic inheritance. This article is part of a Special Issue entitled: Histone chaperones and Chromatin assembly. © 2011 Elsevier B.V. All rights reserved.

1. Introduction The eukaryotic genome is compacted into chromatin, which is composed of basic units termed “nucleosomes” [1]. Each nucleosome consists of an octameric particle of four core histone proteins (H2A, H2B, H3 and H4) that bind and wrap 146 base pairs of DNA around the histone octamer [2]. Histones can be covalently modified by reactions such as acetylation, methylation, phosphorylation, and ubiquitylation [3,4]. These chromatin modifications are often recognized by effector proteins through which they exert their functions [5,6]. In addition to chromatin post-translational modifications, the importance of histone variants has been increasingly demonstrated in recent years [7–9]. Epigenetics is usually defined as the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in the DNA sequence [10]. However, the mechanisms responsible for the inheritance of epigenetic information during mitotic division remain unknown. The inheritance of DNA CpG methylation is the most well understood mechanism; several studies have indicated that there is a semi-conservative segregation of the symmetric CpG methylation and maintenance of the DNA methylation by DNMT1 [11–13] with the assistance of PCNA [14] and UHRF1 [15,16]. Because several histone modifications regulate well-established epigenetic phenomena, including position effect variegation [17–19], Polycomb silencing [20–23], and X inactivation [24,25], researchers are particularly interested in studying the mitotic inheritance of histone modification-mediated epigenetic information.

For mitotic inheritance of histone modification-mediated epigenetic information, numerous models have been discussed in review papers [9,26–34], and several interesting investigations have been recently published [35–41]. Although increasing knowledge has been obtained for histone variants, little information is known regarding whether and/or which histone variants may carry epigenetic information; and how such epigenetic information passes to the daughter cells during mitotic division. In this review, we will discuss the deposition of variant histones and their potential roles in mediating the inheritance of epigenetic information. 2. H3 variants The number of H3 histone variants differs among species. All eukaryotes have a centromere specific H3 (CenH3, or CENP-A in mammals), which contains an amino acid sequence that differs significantly from the other H3 histone variants [7]. In addition to CENP-A, mammals have three ubiquitously expressed H3 variants (H3.1, H3.2, and H3.3) as well as an H3 isoform that is specifically expressed in the testis (H3t) [7]. Recently, two primate-specific H3 variants (H3.X and H3.Y) [42] and a hominid-specific variant H3.5 were identified [43]. Other higher eukaryotes have two noncentromeric H3 variants, H3.3 and H3.1 (identical to mammalian H3.2). Yeast has only one non-centromeric H3, which is similar to H3.3 in higher eukaryotes [7]. 2.1. CenH3

☆ This article is part of a Special Issue entitled: Histone chaperones and Chromatin assembly. ⁎ Corresponding author. Tel.: + 86 10 80728458. E-mail address: [email protected] (B. Zhu). 1874-9399/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagrm.2011.06.007

CENP-A is the first histone variant that was shown to identify specific chromatin regions, namely the centromeres [27]. CENP-A is essential for kinetochore formation and chromosome segregation

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[7,44,45]. CENP-A was identified as an H3 variant during copurification with other core histones [46], although it shares minimal sequence similarity with the other H3 histone variants. The other H3 variants, such as H3.1, H3.2 and H3.3, are at the same molecular weight and differ by only four to five amino acid residues [9]. In contrast, CENP-A has a variable N-terminus, with no sequence similarity to the N-terminal region of the other H3 variants [45]; moreover, CENP-A shares only 50% identity in the histone fold domain with the other H3 histones [47]. 2.1.1. CenH3 deposition and genomic distribution Centromeric DNA is duplicated during the S phase of the cell cycle. However, unlike canonical histones that are incorporated into chromatin during the S phase, newly synthesized CENP-A is deposited during a discrete time period from telophase to the G1 phase in mammals [48]. In yeast, CenH3 is called “Cse4”, and the specific Cse4 chaperone is Scm3 [49]. A crystal structure of the Scm3–Cse4–H4 fusion protein suggests that the complex may form a hexamer (Scm3–Cse4–H4)2 [50]; correspondingly, the formation of a (Scm3–Cse4–H4)2 hexamer was observed in another study under high salt conditions (2 M NaCl) [49]. This suggests that Scm3 may bind and deposit (Cse4–H4)2 tetramers. This is in sharp contrast to Asf1, which is a key histone chaperone for the other H3 histone variants; Asf1 only forms a complex with the H3-H4 dimers, not with the (H3–H4)2 tetramers [51–55]. However, a recent report demonstrated a trimeric crystal structure of a Scm3 fragment associated with a Cse4–H4 dimer, which argues against the (Scm3–Cse4–H4)2 model [56]. Studies have shown that in mammals, Mis16 and Mis18 function as upstream factors that bind and recruit CENP-A to the kinetochore; a double knockdown of the two homologous Mis proteins in HeLa cells abolished localization of CENP-A to the kinetochore [57]. Although Mis16 and Mis18 participate in CENP-A deposition, the direct chaperone that is specific for CENP-A is HJURP [58,59]. The transient appearance of HJURP precisely coincides with the discrete time period for CENP-A deposition, and down regulation of HJURP decreases CENP-A at the centromeres [58,59]. Because HJURP appears at the centromeres slightly later than Mis18, the Mis18 complex may function as the licensing factor for CENP-A deposition, while HJURP likely acts as the direct loading factor for CENP-A [60]. Unlike the Scm3 and Cse4–H4 paradigm in yeast, structural analysis of the human HJURP–CENP-A–H4 trimeric complex indicates that binding of HJURP and CENP-A–H4 dimer prevents the formation of a (CENP-A–H4)2 tetramer, which suggests that CENP-A–H4 is deposited as a dimer rather than a tetramer in mammals [61]. A number of proteins are physically associated with centromeres, such as the NAC complex (including CENP-B, CENP-C, CENP-H, CENPM, CENP-N, CENP-T and CENP-U) [62] and the CENP-H/CENP-I complex [63]; these protein complexes are important for kinetochore assembly and may act upstream or downstream of CENP-A incorporation. Recently, CENP-C and CENP-T have been reported to act downstream of CENP-A incorporation and ectopic tethering of these proteins can induce ectopic kinetochore assembly in the absence of CENP-A incorporation [64]. 2.1.2. Defining centromere identity Once the CenH3 histones are deposited on the centromere, this centromeric state must be stably maintained. A number of proteins, including the CENP-A licensing factor HsKNL2 interacting protein MgcRacGAP (a Rho family activating protein), Ect2 (a Rho family guanine nucleotide exchange factor), and Cdc42 and Rac (two small GTPases) are required to stabilize the newly incorporated CENP-A at the centromeres [65,66]. Because CENP-A occupancy is typically used to define a centromere, these proteins may help to ensure the epigenetic inheritance of the centromeric state by stabilizing CENP-A binding.

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Because CENP-A is exclusively incorporated at the centromeres, the protein must be removed after incorrect incorporation at noncentromere chromatin regions. The Cse4 specific E3 ubiquitin ligase Psh1 mediates the degradation of non-centromeric Cse4 [67,68]. Although the data clearly indicates that Psh1 plays a role in preventing Cse4 mislocalization, parallel mechanisms must exist because Psh1 deletion displayed a very mild phenotype unless Cse4 was massively over expressed [67,68]. The small GTPase and E3 ubiquitin ligase additionally help to maintain the epigenetic state of centromeres, although CENP-A appears to be the most important factor. CENP-A's relatively long loop 1 region in the histone fold domain makes a large area of contact with the centromeric DNA and contributes to the binding specificity [69–71]. The structure of the human (CENP-A–H4)2 heterotetramer shows a rotated CENP-A–CENP-A interface and a strong hydrophobic interaction between CENP-A and H4, which contributes to the unconventional shape of the CENP-A-containing nucleosomes [72]. Interestingly, human neocentromeres can be formed at genomic regions that lack the satellite DNA sequences that are normally present at the centromeres [73], and similar events have been observed in fission yeast [74] and plants [75]. Thus, CENP-A binding, rather than the DNA sequence, appears to be a more important determinant for defining the centromere [76]. Unlike other histones, CENP-A is not replaced by protamines during mammalian spermatogenesis, which also suggests that CENP-A plays an important role in defining the centromere [77]. 2.1.3. Models for restoring CenH3 nucleosomes or the epigenetic inheritance of centromeres Extensive investigations regarding CenH3 have suggested several models for CenH3-containing nucleosome structures, including: 1) an octameric nucleosome containing two copies of H2A, H2B, Cen-H3 and H4, with DNA wrapped in left-handed orientation [62,70,72,78–80]; 2) a tetrasome containing two copies of CenH3 and H4 but lacking the H2A– H2B dimers [81]; 3) a hexasome containing two copies of Scm3, CenH3 and H4 [49]; and 4) a hemisome that contains only one copy of H2A, H2B, CenH3 and H4, with DNA wrapped in a right-handed orientation [82,83]. Despite the uncertainty regarding CenH3 nucleosome composition and structure, it is generally agreed that CenH3-containing nucleosomes must be restored to maintain the identity of the centromeres after DNA duplication. The incorporation of newly synthesized CenH3 begins during telophase, which occurs much later than centromeric DNA duplication. Therefore, CenH3 is in shortage for a considerably long period of time. Several models have been proposed to explain the chromatin states of the centromeres during this period and define the mechanisms by which the CenH3-containing nucleosomes are restored. 1) After DNA replication, part of the centromeric region is temporarily occupied by H3.1 nucleosomes, and CenH3 nucleosomes replace these transient nucleosomes during the later stages in of the cell cycle (Fig. 1, left). Based upon this model, the most critical problem is how to ensure that the CenH3 nucleosomes only replace the H3.1 nucleosomes at the centromeres. Distinct modification patterns on the interspersed H3.1 nucleosomes at the centromeric regions [84,85] and the remaining CenH3 nucleosomes at the centromeric regions may identify these regions for CenH3 replacement. In mammals, CENP-A and H3.1 nucleosomes are interspaced at the centromeric regions; however, the CENP-A nucleosomes are spatially continuous and are often oriented in the same direction, which aids in kinetochore formation [86]; therefore, epigenetic information may be provided by the spatially proximal CENP-A nucleosomes to guide the incorporation of newly synthesized CENPA. If this hypothesis is correct, the CenH3 deposition machinery may be able to recognize this genomic signal. Although we generally prefer this model, we must point out that it is incompatible with the data for budding yeast, where each centromere is only composed of one nucleosome [87].

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Fig. 1. Models for CENP-A inheritance at the centromere. Left: H3.1 nucleosomes are incorporated into the centromeric regions during DNA replication, and the CENP-A nucleosomes are later incorporated and replace the H3.1 nucleosomes. Middle: DNA replication forms gaps that are devoid of nucleosomes during the S phase, and these gaps are later filled with newly synthesized CENP-A nucleosomes. Right: DNA replication leads to the formation of hemisomes at the centromeric regions, and newly synthesized CENP-A-H4 dimers pair with the existing hemisomes to form hybrid nucleosomes. Note: the H2A-H2B dimers were omitted from this illustration for simplicity.

2) During DNA replication, gaps are created at the centromeric regions that are not filled with canonical nucleosomes and only become occupied after the incorporation of CenH3 nucleosomes (Fig. 1, middle). However, long stretches of DNA with reduced nucleosome protection at the centromeric regions may not be preferable [60]. In addition, this model is also incompatible with the data for budding yeast for the same reason mentioned with model 1. 3) During DNA replication, the CenH3 nucleosomes split into twohalves, where each half occupies one sister chromatid and can easily incorporate newly synthesized CenH3 molecules. Consistent with this model, CenH3 nucleosomes were reported to be at the half height of the canonical nucleosomes [81,82], which suggests a “hemisome” model for CenH3 nucleosome structure. In this model, epigenetic information may be maintained at the mono-nucleosome level (Fig. 1, right), which agrees well with the data for budding yeast centromere identity. 2.2. H3.3 Histone variant H3.3 differs from the canonical H3 by only four amino acid residues, where three of these residues are clustered in the α2 helix of the histone fold domain and the other residue is in the N-terminal tail [9]. Unlike H3.1, which is strictly expressed and deposited during S phase, H3.3 is expressed and deposited throughout the cell cycle [88]. The three distinct amino acid residues in the α2 helix are responsible for the replication-independent incorporation of H3.3 [88], and H3.3 histones are enriched at transcriptionally active regions [88–90] as well as telomeres and pericentromeric regions [91–94]. 2.2.1. H3.3 deposition and genomic distribution Biochemical purification of non-chromatic H3 histones in HeLa cells showed that the canonical H3 histones are deposited by the CAF1 complex in a replication-dependent manner, whereas H3.3 histones are deposited by the HIRA complex in a replication-independent manner [51]. Both complexes contain HAT1, which corresponds with previous observations that pre-deposited histones are transiently

acetylated. The histone chaperone Asf1 is also present in both complexes, which agrees with previous studies that indicated that Asf1 participates in chromatin assembly [95–98]. Recently, several independent studies have shown that the ATRXDAXX complex and DEK are chaperone proteins that play a role in H3.3 deposition at discrete chromatin regions, including telomeres and pericentromeric regions [91–94]. These studies are particularly interesting because they indicate that H3.3, although traditionally thought to be a marker of euchromatin [8], is also present at heterochromatic regions. The H3.3 chaperones that have been identified play a role in H3.3 replication-independent deposition. H3.3 can also be deposited in a replication-dependent manner [99,100], although the chaperone proteins responsible for replication-dependent H3.3 deposition are unknown. It is possible that the CAF complex can deposit both H3.1 and H3.3 histones in a replication-dependent manner because the yeast CAF complex can deposit the only non-centromeric H3, which is similar to H3.3 [8].

2.2.2. H3.3 mediated epigenetic inheritance The potential of H3.3 to mediate epigenetic inheritance can be divided into two questions: 1) whether or how H3.3 histone modifications are maintained in a mitotically heritable manner and 2) whether or how H3.3 histones are incorporated at specific chromatin regions in a mitotically heritable manner. Histone variants differ from each other not only in their chromatin location, but also in their post-translational modifications [101]. For example, compared with the canonical H3 histone, H3.3 histones are enriched in post-translational modifications that correlate with gene expression, such as H3K4 and H3K36 methylation, as well as H3K9, H3K18, and H3K23 acetylation [54,102–106]. This is consistent with previous observations that the H3.3 histones are enriched at transcriptionally active regions of the genome [88–90]. However, there is little evidence to suggest that the H3.3 histones are more favorable substrates for the enzymes that mediate these modifications. The enrichment of these active modifications on H3.3 histone

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may simply be because H3.3 deposition and active histone modifications are both independently correlated with transcriptional activity. A semi-conservative segregation of the (H3–H4)2 tetramers, followed by templated modification copying events, was once a model favored for the mitotic inheritance of histone modificationmediated epigenetic information. However, most lysine methylations do not have to be symmetrical within each nucleosome [41], and canonical (H3–H4)2 tetramers do not split during replicationdependent chromatin assembly [35]. These recent findings negate this model as the general mechanism for mitotic inheritance of histone modification-mediated epigenetic information [33,34,107]. Although a fraction of (H3.3–H4)2 tetramers split in mammalian cells [35] and similar events occur for the H3.3-like histones in budding yeast [108], it is unlikely that these events mediate a faithful duplication of histone modifications within certain subpopulations of mono-nucleosomes. On the other hand, the H3.3 histones are clearly enriched at certain chromatin regions, including actively transcribed genes [88–90] and heterochromatic regions, such as the telomeres and pericentromeric regions [91,92,94,109]. However, it remains unclear whether H3.3 histone localization contributes to the transcriptional status of the underlying DNA. A number of studies suggest that H3.3 plays a role in maintaining the transcriptional status of the target loci. Nuclear transfer experiments in Xenopus laevis demonstrated that the expression of the donor-originated MyoD gene can persist over 24 mitotic divisions and that this epigenetic memory is dependent upon H3.3 lysine 4 methylation [110,111]. However, the loss of both H3.3 genes in flies leads to a mild transcriptional defect with partial lethality, and most of the surviving H3.3-null flies develop normally, except for the male germline [112]. These results suggest that H3.3 histones are not essential for maintaining the epigenetic status of transcriptionally active genes, which is consistent with the idea that H3.3 enrichment at euchromatic regions is a consequence, rather than a determinant, of transcriptional activity. In contrast, H3.3 histones were reported to be critical for the formation of pericentromeric heterochromatin [109] and the maintenance of the telomeres [88,93]. Thus, the data indicate that H3.3 histones may play a role in epigenetic silencing. 3. H2A variants The H2A and H3 histones are structurally similar [113] and have several variant forms [7,47]. In addition to the canonical histone H2A, four H2A variants have been reported in mammals (H2A.Z, H2A.X, marcoH2A and H2A.Bbd) [47]. 3.1. H2A.Z H2A.Z is highly conserved throughout evolution, it has a single evolutionary origin and remains distinct from all other H2A variants [47]. This specialization suggests that H2A.Z has a distinct function from all other H2A variants. H2A.Z differs from canonical H2A and other H2A variants mainly in its “docking” domain in the C-terminus and in the L1 loop where two H2A molecules contact each other [2,69,114]. 3.1.1. H2A.Z deposition and genomic distribution The SWR1 complex, which is an ATP-dependent chromatinremodeling complex, was the first identified H2A.Z chaperone that mediates H2A.Z deposition [115–117]. Subsequently, the Nap1 and Chz1 histone chaperones also associate with H2A.Z–H2B dimers, and these chaperones were proposed to transfer the H2A.Z–H2B dimers to the SWR1 complex to exchange chromatin H2A-H2B dimers with H2A.Z–H2B dimers [118]. Recent studies have indicated that Nap1 and Chz1 are not functionally redundant. Nap1 mediates the nuclear import of cytosolic H2A.Z–H2B, whereas Chz1 presents the H2A.Z–

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H2B dimers to the SWR1 complex for final deposition [119]. A recent study has presented a detailed molecular mechanism of SWR1mediated H2A.Z deposition [120]. SWR1 replaces H2A–H2B with H2A.Z–H2B in a stepwise manner, one copy of the H2A.Z–H2B dimer at a time, which leads to the formation of intermediate hybrid nucleosomes that contain both H2A and H2A.Z [120]. Interestingly, nucleosome-dependent SWR1 ATPase activity is dependent upon the substrate composition, which indicates that the SWR1 complex can sense the substrate status and receive a “mission accomplished” signal to terminate its activity [120]. Genome-wide nucleosome occupancy studies in yeast and flies have been performed to assess the distribution of H2A.Z nucleosomes. The H2A.Z nucleosomes are localized to both sides of “nucleosomefree regions (NFR)” in yeast near the transcription start sites (− 1, + 1 nucleosome) [121,122], while the fly H2A.Z nucleosomes are predominantly enriched just downstream of the transcription start sites (+1 nucleosome) [123]. Because the NFRs in yeast are precisely located between two well-positioned H2A.Z nucleosomes, they may play a role in the H2A.Z localization pattern. In yeast, the RSC chromatin-remodeling complex mediates NFR formation at promoters by displacing nucleosomes at the NFR, and the RSC is required for deposition of the flanking H2A.Z nucleosomes [124]. A previous study has suggested that in mammals, the “NFRs” at the transcription start sites were suggested to be consequence of losing the highly labile nucleosomes consisted of both H2A.Z and H3.3 located at NFRs [125]. The specific localization pattern of H2A.Z nucleosomes near the transcription start site has been proposed to be an epigenetic marker for directing or regulating the positioning of downstream nucleosomes [126–128]. Therefore, ensuring the correct deposition of H2A.Z nucleosomes is crucial for the maintenance of epigenetic modifications at the transcription start site. Recently, the INO80 complex, which is another ATP-dependent chromatin remodeling complex that is closely related to the SWR1 complex, was reported to mediate the replacement of H2A.Z with canonical H2A to ensure proper H2A.Z distribution at transcription start sites in yeast [129]. 3.1.2. H2A.Z mediated epigenetic inheritance Compared to the (H3–H4)2 tetramers, the H2A–H2B dimers are much more mobile [130]. Nucleosomes frequently exchange their H2A–H2B dimers, but rarely exchange their (H3–H4)2 tetramers [35]. Additionally, lysine methylations, which are thought to be the most stable histone modification [131], predominantly occur on the H3 or H4 histones [3,4]. Thus, the H2A and H2B histones may not be good candidates for the propagation of epigenetic information. However, a number of studies discussed below suggest that H2A.Z may carry important epigenetic information and maintain the chromatin transcriptional status. Transcriptional memory. The yeast genes INO1 and GAL1 localize to the nuclear periphery upon transcriptional induction. After a short period of transcriptional repression, the nuclear peripheral INO1 and GAL1 genes are rapidly reactivated, but not in Htz1 mutant strains (which cannot encode H2A.Z), which suggests that H2A.Z mediates epigenetic memory of the previous transcriptional state [132]. Interestingly, transcriptional memory of the yeast GAL genes requires SWI/SNF activity [133], and SWI/SNF recruitment is dependent upon H2A.Z [134], which again suggests that H2A.Z mediates epigenetic transcriptional memory. Heterochromatin formation and maintenance. Upon differentiation of cells at the murine inner cell mass (ICM), H2A.Z is first enriched at pericentromeric heterochromatin and subsequently enriched at other chromatin regions. Moreover, H2A.Z directly interacts with the pericentromeric heterochromatin protein INCENP in vivo[135]. H2A.Z depletion caused genome instability and disruption of HP1α localization at the pericentromeric regions, which suggests that HP1α function and pericentromeric heterochromatin identity are regulated by H2A.Z during early embryonic development in mice [136]. In yeast,

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Htz1 acts together with a boundary element to prevent the spread of heterochromatin. As in htz1Δ cells, Sir2 and Sir3 spread from telomeric regions to flanking eukaryotic regions and lead to ectopic heterochromatin formation [137].

macroH2A is enriched at developmental genes in human pluripotent cells in males and regulates the timing of HoxA activation. The macroH2A distribution pattern at the Hox loci overlaps with PRC2; therefore, marcoH2A is potentially an epigenetic regulator of key developmental genes and may cooperate with PRC2 [152].

3.2. H2A.X H2A.X is present in nearly all eukaryotes, except nematodes [47]. This histone variant has a histone fold domain that is similar to the canonical H2A, although it has a unique C-terminal motif termed SQ(E/D)Ф (where Ф represents a hydrophobic residue) [47,138]. The H2A.X serine residue at the γ-position of the C terminus can be phosphorylated (termed γ-H2A.X) after DNA double-strand breaks (DSB) occur, which has been previously described [139,140]. 3.2.1. H2A.X deposition and genomic distribution Previous studies have shown that H2A.X plays a role in DSB repair; therefore, H2A.X is viewed as the “histone guardian of the genome” [141]. Because DSB can potentially occur anywhere in the genome, H2A.X deposition should be random. Although the FACT protein complex can mediate the exchange of γ-H2A.X-H2B with unmodified H2A.X-H2B [142], no specific de novo deposition chaperone for H2A.X has been identified. Because of the overall sequence similarity between H2A.X and canonical H2A [47,138], we hypothesize that the same assembly factor mediates H2A.X and canonical H2A deposition. 3.2.2. The role of H2A.X in meiotic silencing Aside from the well known function of H2A.X in DSB repair, H2A.X has also been implicated to play a role in meiosis, growth, tumor suppression and immune receptor rearrangements [141]. Interestingly, H2A.X knockout mice are sterile [143]. In wild type mice, during the pachytene stage of spermatogenesis γ-H2A.X is enriched at the sex chromosomes to initiate meiotic sex chromosome inactivation (MSCI) and X and Y chromosome condensation, which leads to the formation of a partially paired sex body. In H2A.X-null mice, this entire process was impaired [143]. Additionally, previous studies have indicated that γ-H2A.X also plays a role in meiotic silencing of unpaired chromosomes in female mice [144]. H3.3-deficient male flies have decreased fertility [112], and it is interesting to speculate whether these meiotic defects are the results of impaired meiotic silencing and whether H2A.X and H3.3 play cooperative roles in these events. 3.3. macroH2A macroH2A is a vertebrate-specific H2A variant that contains two distinct domains [145]. Although the N terminal region of macroH2A is similar to canonical H2A, macroH2A contains a large (200 residue) C terminal domain termed “the macro domain” that shares no sequence similarity with any other histone [47]. In mammals, macroH2A is enriched on the inactive X chromosomes in females [146]. Interestingly, macroH2A is re-localized from centrosomes to inactive X chromosomes, and this re-localization is dependent on Xist expression after X inactivation initiation [147,148]; however, X inactivation initiation is not dependent on macroH2A. Therefore, macroH2A is thought to be an epigenetic marker of X inactivation and may contribute to the maintenance of an inactive X chromosome. Several studies have suggested potential mechanisms where macroH2A represses gene expression. A previous study has shown that the Cterminal macro domain of macroH2A interferes with the binding of transcription factors, and the N-terminal domain impedes chromatin remodeling via SWI/SNF [149]. In addition, macroH2A can mediate gene silencing by inhibiting the catalytic activity and substrate binding capacity of PARP1, which is a nuclear enzyme that is involved in gene activation [150,151]. Moreover, additional studies have indicated that macroH2A is involved in autosomal gene silencing.

3.4. H2A.Bbd H2A.Bbd is the most recently discovered H2A variant; this histone variant has a truncated C-terminal docking domain [153] and was named because of its unique genomic distribution, where it is deficient in inactive X chromosomes (bar body deficient). The H2A.Bbd nucleosome binds only 116 base pairs of DNA and is less stable than the canonical nucleosome [154,155]. H2A.Bbd lacks a small acidic region on the nucleosome surface that is involved in transcriptional repression and also lacks K119, which is often ubiquitinated on canonical H2A at transcriptionally inactive regions [156]. The unique subnuclear localization and key features of H2A.Bbd suggest that it is involved in gene activation. 4. H4 and H2B histones Unlike the H3 and H2A histones, which have several variants with different functions, no ubiquitously expressed H4 and H2B variants have been reported thus far. Nevertheless, a few tissue-specific H2B isoforms have been reported, including sperm specific H2B variant (spH2B), testis specific H2B variants TH2B and H2BFWT [157]. Interestingly, TH2B was proposed to be a platform in specifying pericentric heterochromatin during late spermiogenesis [158], which maybe a good target in studying the inheritance of epigenetic states of pericentric heterochromatin during meiosis. On the other hand, H2BFWT appears to be enriched at telomere interstitial blocks, and it has been proposed that H2BFWT may serve as an epigenetic marker telomeric identity in testis [159]. 5. Perspectives Histone variants are currently the new frontier of chromatin biology. However, several important questions regarding the mechanisms behind epigenetic inheritance and stability remain. More studies are needed to clarify which histone variants are involved in epigenetic regulation. Because a key criterion of epigenetics is that the information is heritable, it is critical to discover which histone variants play a role in this process and which of their mediated functions are inherited during mitotic/meiotic division. The post-translational histone modifications often recruit the associated effector proteins to exert a function [5,6]. However, few proteins have been discovered that can bind to and specifically recognize the variant histones in chromatin context. Several pressing questions remain, including “How do the histone variants function once they are deposited?” and “Are the histone variants recognized by proteins factors like the histone modifications, or do they function solely by altering the intrinsic properties of the underlying chromatin?” Acknowledgments The research of B. Z. is supported by grants from the Chinese Ministry of Science and Technology (2011CB965300 and 2007AA02Z1A6). References [1] R.D. Kornberg, J.O. Thomas, Chromatin structure; oligomers of the histones, Science 184 (1974) 865–868. [2] K. Luger, A.W. Mader, R.K. Richmond, D.F. Sargent, T.J. Richmond, Crystal structure of the nucleosome core particle at 2.8 A resolution, Nature 389 (1997) 251–260.

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