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DOI 10.1002/pmic.201300435

REVIEW

Posttranslational modifications of human histone H3: An update Yan-Ming Xu, Ji-Ying Du and Andy T. Y. Lau Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China

Histone proteins, the fundamental components of chromatin, are highly conserved proteins that present in eukaryotic nuclei. They organize genomic DNA to form nucleosomes, the basic units of chromatin. PTMs of histones play essential roles in many biological processes, such as chromatin condensation, gene expression, cell differentiation, and apoptosis. With the advancement of proteomic technology, a growing number of histone PTMs have been identified, including ADP-ribosylation, biotinylation, citrullination, crotonylation, O-GlcNAcylation, glutathionylation, succinylation, and so on. Because of the fast growing list of these PTMs in just a few years, the functions of these marks are being studied intensively. As histone H3 has the most number of PTMs among the histone members, in this review, we would like to present the overall concepts of the more familiar PTMs as well as discussing all the recently identified yet less well-known PTMs on human histone H3.

Received: October 1, 2013 Revised: May 30, 2014 Accepted: July 4, 2014

Keywords: Cell biology / Histone H3 / Mass spectrometry / Novel posttranslational modifications / Tandem mass spectrometry

1 Correspondence: Professor Andy T. Y. Lau, Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, 22 Xinling Road, Shantou, Guangdong 515041, P. R. China E-mail: [email protected] Fax: +86-754-8890-0437 Abbreviations: ac, acetylation; ar, ADP-ribosylation; AURK, aurora kinase; bio, biotinylation; CARM, coactivator-associated arginine methyltransferase; ChIP, chromatin immunoprecipitation; ChIP-seq, chromatin immunoprecipitation sequencing; CHK, checkpoint kinase; ci, citrullination; cr, crotonylation; Dnmt1, DNA (cytosine-5)-methyltransferase 1; DSBs, doublestrand breaks; ER␣, estrogen receptor ␣; ESC, embryonic stem cell; EZH, enhancer of zeste homolog; fo, formylation; glc, O-GlcNAcylation; glu, glutathionylation; GSNO, nitrosoglutathione; HAT, histone acetyltransferase; HCF1, host cell factor 1; HCS, holocarboxylase synthetase; HDAC, histone deacetylase; hmc, 5-hydroxymethylcytosine; HP1, heterochromatin protein 1; JAK, Janus kinase; KMT, lysine methyltransferase; mc, 5-methylcytosine; me, methylation; me1, monomethylation; me2, dimethylation; me3, trimethylation; me2a, asymmetric dimethylation; me2s, symmetric dimethylation; OGA, O-GlcNAcase; O-GlcNAc, O-linked ␤-N-acetylglucosamine; OGT, O-GlcNAc transferase; PAD, peptidyl arginine deiminase; PARP, poly(ADP-

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Introduction

Histone proteins, the fundamental components of chromatin, are essential for organizing genomic DNA to form nucleosomes in eukaryotic nuclei. The nucleosome consists of a histone octamer (two copies each of four core histones H2A, H2B, H3, and H4) wrapped by approximately 147 bp of DNA. The core histones are predominantly globular except for their unstructured N- or C-terminal tails that extend outside the nucleosome core [1]. The most striking feature of histones is that there exists large numbers and different types of PTMs on them, such as acetylation (ac), methylation (me), phosphorylation (ph), ubiquitylation (ub), and so on. These PTMs play important roles in the regulation of diverse cellular processes, including chromatin condensation, gene expression, cell differentiation, and apoptosis [1].

ribose) polymerase; PKC, protein kinase C; ph, phosphorylation; pr, propionylation; PRC, polycomb repressive complex; PRK1, PKC-related kinase 1; PRMT, protein arginine methyltransferase; SAM, S-adenosylmethionine; SIRT1, sirtuin 1; succ, succinylation; TET, ten eleven translocation; ub, ubiquitylation; Uhrf1, ubiquitinlike with PHD and ring finger domains 1

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In eukaryotes, histone variants exist based on the differences of their primary amino acid sequences. These variants have different regulatory mechanisms for their expressions, depositions, as well as genome occupancies [2]. There are several H3 variants identified in Homo sapiens: (i) the canonical variants: H3.1 and H3.2 and (ii) the replacement variants: H3.3, the centromere-specific variant CENP-A [3], the testis-specific histone H3t [4], and two newly characterized primate-specific H3 variants, H3.X and H3.Y [5]. H3.1, H3.2, and H3.3 are the more abundantly expressed histone H3 variants with more than 96% (H3.1/H3.2 vs. H3.3) to 99% (H3.1 vs. H3.2) of amino acid sequence similarity. Because of the high amino acid homology among these histone H3 variants, the same PTM marks would likely be decorated on the same conserved amino acid residues. However, because of the different occupancy of H3 variants in the genome, some PTMs might therefore be more enriched on a particular region while some are not. In general, H3.3 is associated with euchromatin and enriched in PTMs for transcriptional activation. Although H3.2 and H3.1 are localized to heterochromatin, H3.2 is enriched in PTMs associated with gene silencing, while H3.1 is enriched in PTMs associated with gene activation and gene silencing, suggesting that these human H3 variants likely have separate biological functions [6–9]. Because H3.1, H3.2, and H3.3 are the more extensively studied histone H3 variants with very high degree of amino acid sequence similarity, in this review, we therefore intend to focus and present the latest PTM information among these three variants. PTMs of histones are crucial for performing their functions. Therefore, it is of great importance to comprehend this epigenetic regulation. There are many methods to determine histone PTMs, including MS-based method such as MS/MS, and non-MS-based methods such as amino acid sequencing, peptide mapping, site-directed mutagenesis, and antibody-based method. In the past, the traditional way of studying histone PTM relied heavily on generating a site-specific modification-detecting antibody before the PTM under question can be validated at cellular level. This antibody-based method not only may cause problems such as antibody cross-reactivity and epitope occlusion through interference by neighboring modifications, but also could only detect limited number of modification sites at a single time [10], while MS-based proteomic approach can avoid these problems [11]. Recently, high-resolution NMR spectroscopy was also being used as another method to study the PTMs of histones [12]. Suffice it to say, by utilizing multiple approaches, and with the advancement of proteomic technology, a growing number of novel PTMs on histones have been identified, yet, the ultimate functions associated with these PTMs still require more in-depth study. For the vast emerging literatures published in just the few years, in this review, we intend to present the overall concepts of the well-characterized PTMs (such as ac, me, and ph) in the beginning and then move forward gradually to all the recently identified yet less well-known PTMs on human histone H3 (Fig. 1).  C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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PTM marks identified on human H3 variants and the resulting functions

Up to now, at least 17 kinds of modification on more than 30 amino acid residues of human histone H3 variants have been reported, including acetylation (ac), ADP-ribosylation (ar), biotinylation (bio), citrullination (ci), crotonylation (cr), formylation (fo), O-GlcNAcylation (glc), glutathionylation (glu), methylation (me), phosphorylation (ph), propionylation (pr), succinylation (succ), and ubiquitylation (ub) (Fig. 2). Plenty of studies have revealed that PTMs of histone H3, especially those located in the N-terminal tails, play a crucial role in diverse cellular processes as will be discussed in the following sections. 2.1 Acetylation Acetylation was first discovered on lysine residues of histones for more than four decades and widely studied [13]. It is catalyzed by a special category of enzymes called “histone acetyltransferases” (HATs) such as p300 and CREB-binding protein, with acetyl-CoA as the acetyl group donor. Lysine ac of protein is a dynamic PTM that is known to play a vital role in regulating chromatin structure and transcriptional activity. Histone acetylation marks are removed by the class of enzymes named “histone deacetylases” (HDACs) such as sirtuin 1 (SIRT1) [14, 15]. It is generally accepted that histone acetylation by HATs is associated with transcriptional activation, whereas histone deacetylation by HDACs promotes chromatin condensation and transcriptional repression [14, 15]. Histone acetylation neutralizes the positive charge of lysine residues, weakening charge-dependent interactions between histones and nucleosomal DNA, linker DNA or adjacent histones, and thus increasing the accessibility of DNA to the transcriptional machinery, providing binding sites for transcriptional activation complexes that possess bromodomains, which bind acetylated lysine residues. Histone deacetylation represses transcription through an inverse mechanism involving the assembly of compact and higher order chromatin structure and the exclusion of bromodomain-containing transcriptional activation complexes [16, 17]. Histone lysine acetylation also functions in other cellular processes that require DNA access, such as before DNA replication because charge neutralization of lysines is important for relaxing histone-DNA contacts [18]. Moreover, histone acetylation also occurs at DNA double-strand breaks (DSBs) and may therefore be used to increase DNA access for repair factors [19]. For more detailed perspective of the related processes of histone acetylation and deacetylation, we refer the reader to the following reviews [14, 15, 20, 21]. It is well-documented that acetylations of H3 at residues K9, K14, K18, K23, K27, and K36 are related to transcriptional activation, and plenty of classical experiments have already proven the biological significance of these PTMs in vivo [1,22–26]. With the use of high-resolution MS analysis, it would become possible to explore the potential PTM sites in www.proteomics-journal.com

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Figure 1. Chemical structures of the posttranslationally modified residues of the less wellknown PTMs on histone H3. The peptide backbones were highlighted in gray while the posttranslationally added parts were encircled by dotted lines. For ubiquitylated lysine, the diglycine peptide bonds at the C-terminal end of ubiquityl group are also depicted.

a global way. In 2007, through MS and immunobiochemical approaches, Garcia et al. not only provided the confirmation of some previously reported PTMs in human cells (such as H3K9ac, K14ac, K18ac, K23ac, K27ac, and K36ac), but also reported the existence of new acetylation marks on H3K4, K56, and K79 [27]. Further genome-wide study has also shown that H3K4ac is indeed an abundant mark and enriched at the transcription start site and along gene bodies, suggesting its role in transcriptional activation [22]. Using MS and genome-wide analyses, it was found that K56ac is present in human embryonic stem cells (ESCs), and overlapping strongly at active and inactive promoters with the binding of the key regulators of pluripotency, NANOG, SOX2, and OCT4 [28]. Upon cellular differentiation, H3K56ac relocates to developmen-

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tal genes. Thus the H3K56ac state more accurately reflects the epigenetic differences between human ESCs and somatic cells than other active histone marks such as H3K4me3 and H3K9ac, and is involved in the human core transcriptional network of pluripotency [28]. During DNA damage, H3K56 acetylation is increased at the DNA repair sites. It is also colocalized with other proteins involved in DNA damage signaling pathways such as phospho-(ataxia telangiectasia mutated, short name as ATM), checkpoint kinase 2 (CHK2) and p53, demonstrating its involvement in DNA damage repair [29]. For H3K79ac, its function is yet to be uncovered but since its level is present at low abundance, which may suggest that this mark may counteract methylation at this lysine [27].

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Figure 2. PTMs of human histone H3. Up to now, there are at least 17 kinds of modification on more than 30 amino acid residues of histone H3. Data were summarized from recent literature from NCBI and referenced from UniProtKB (Protein knowledgebase of UniProt), and PhosphoSitePlus (http://www.phosphosite.org).

Further to the C-terminal region, it has been found that acetylation of H3K122 occurs. H3K122 is located on the dyad axis of the nucleosome, the part of the lateral surface where histone-DNA binding reaches its maximum extent [30]. Acetylation of H3K122 can be induced by nuclear hormone receptor signaling. H3K122ac is sufficient to stimulate histone eviction from and transcription of chromatin, which is different from H3 acetylation at its N-terminal tail [31]. Last but not the least, there is a new report by Garcia’s group on histone acetylation. Using high-sensitive nanoLC-MS/MS analysis and immunodetection assays, they reported the existence of a novel class of histone PTMs, that is, serine, threonine, and tyrosine O-acetylation. Interestingly, these unique marks were only found on histone H3 across eukaryotic organisms. Specifically, they demonstrated that H3S10ac occurs in human cells, and is potentially linked to cell cycle progression and cellular pluripotency. However, the enzyme that regulates this mark is yet to be discovered [32]. The data from Garcia’s group also give us the notion that MS-based proteomic approach is a very powerful tool for PTM interrogation and that acetylation, as well as other types of PTM, might potentially be decorated on any possible amino acids of histone. As in the case of H3S10, which has now been demonstrated to be acetylated, suggesting the existence of unexpected regulator(s) of this mark in vivo.

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2.2 Methylation Methylation can take place on both lysine and arginine residues, and these modifications are major determinants for the formation of active and inactive regions of the genome, depending on the sites that are methylated and also the degree of methylation [33]. Lysine methylation is one of the most stable histone marks and lysine residues can undergo monomethylation (me1), dimethylation (me2), and trimethylation (me3). These modifications are carried out by a category of enzymes called “lysine methyltransferases” (KMTs) with S-adenosylmethionine (SAM) as the methyl donor [34]. Mono-, di-, or trimethylation of the lysine on histone does not affect its positive charge, therefore, the effect of methylation on nucleosome dynamics is expected to be less direct than other PTM marks (such as acyl lysine marks). Histone arginine residues can undergo monomethylation (me1) and dimethylation (me2) by “protein arginine methyltransferases” (PRMTs) and the methyl donor in also SAM [35]. Dimethylation can also occur either in a symmetric or asymmetric manner. Symmetric dimethylation (me2s) refers to methylations on two separate nitrogens (N, N ) whereas asymmetric dimethylation (me2a) means methylations on the same nitrogen atom (N, N) on the side chain of the arginine residue. Yet, much less is known about the effects of histone arginine methylation on nucleosome dynamics. And

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of course, histone methylation marks are removed by the class of enzymes named “histone demethylases” such as lysinespecific demethylase 1 and Jumonji domain-containing protein 6, which are demethylases that remove methyl groups from methylated lysines or arginines, respectively [36, 37].

2.2.1 Lysine methylation Lysine methylation is one of the most abundant PTMs on histones. Monomethylation often acts as a substrate for enzymes that further catalyzing di- and trimethylation at the same residue. The majority of histone KMTs [such as “mixedlineage leukemia”, Suv39, and G9a] contain a SET domain. The SET domain is an evolutionarily conserved, 130 amino acid sequence motif, which catalyzes the transfer of the methyl group from the cofactor SAM to the lysine residue [38]. For more detailed perspective of the related processes of histone lysine methylation, we refer the reader to the following reviews [33, 34]. It is well-known that methylation of H3 at lysine residues 4 and 36 are mainly associated with gene activation, whereas at lysine residues 9 and 27 are involved in transcriptional repression [27, 39]. These modifications are critical in differentiating euchromatin and heterochromatin territories. Studies on H3K4me3 and H3K27me3 marks in stem cells have proposed the idea of “bivalent chromatin domains” as generich regions that harbor both these marks and are poised for transcriptional activation or repression of key developmental genes [40, 41]. Trimethylation of H3K27 mediated by polycomb repressive complex 2 (PRC2) has been linked to ESC identity and pluripotency [42]. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of PRC2, has been reported as the sole histone methyltransferase that methylates H3K27. Recenly, it has been shown that EZH1 also mediates methylation on H3K27 and complements EZH2 in maintaining stem cell identity and executing pluripotency [43]. Several lysine methylation marks occur in the globular domain/core region of H3 (K56, K64, and K79). It has been recently demonstrated that H3K56me1 regulates DNA replication through interaction with proliferating cell nuclear antigen and is catalyzed by the KMT G9a [44]. Although low level of H3K56me3 has been first identified by the use of MS analysis back in the year of 2007 [27], it was not until recently that the role of H3K56me3 revealed by Hake’s group. They demonstrated that this mark is a novel heterochromatic mark that largely but not completely overlaps with H3K9me3 in both regulation and localization, and H3K56me3 is catalyzed by the KMT Suv39 [45]. H3K64me3 has also been identified that is preferentially localized to repressive chromatin, and it was hypothesized that this mark helps to secure nucleosomes, and perhaps the surrounding chromatins, in an appropriately repressed state during development [46]. However, the writer(s) and potential eraser(s) to this mark have not been identified.  C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Last but not the least, H3K79 also undergoes methylation by the evolutionarily conserved histone methyltransferase DOT1L. Unlike other KMTs, DOT1L does not contain a SET domain, but it specifically methylates nucleosomal histone H3 and is correlated with transcriptional activation [47, 48]. Methylated H3K79 is also associated with DNA DSB responses and is a specific target for tumor suppressor p53binding protein 1, a conserved checkpoint protein with properties of a DNA DSB sensor [49]. Yet, the corresponding demethylase for methylated H3K79 is currently unknown. Some novel lysine methylation marks have been proven to be existed on human H3 in vivo by MS and/or large-scale analyses, that is, H3K14me1/2/3, H3K18me1, H3K23me1, H3K37me1, H3K64me1, and H3K122me1, but the functions of these PTMs are currently unknown [8, 27, 50–52].

2.2.2 Arginine methylation Similar to lysine, arginine is a positively charged amino acid; it works by mediating the hydrogen bonding and aminoaromatic interactions. Arginine methylation is known to play important and dynamic roles in gene regulation. Arginine residues can be methylated by PRMTs, which can be divided into two types: type I PRMTs, catalyze the monomethylation and asymmetric dimethylation of arginine residues; while type II PRMTs, facilitate the formation of monomethylated and symmetric dimethylated arginines [33, 35]. For more detailed perspective of the related processes of histone arginine methylation, we refer the reader to the following reviews [33, 35]. Among the PRMTs, it has been shown that PRMT4 [also called coactivator-associated arginine methyltransferase 1 (CARM1)] promotes transcriptional activation by catalyzing the monomethylation of H3R2, R17, and R26, as well as asymmetric dimethylation of R17 (H3R17me2a) and R26 (H3R26me2a), whereas asymmetric dimethylation of H3R2 (H3R2me2a) by PRMT6 and symmetric dimethylation of H3R8 (H3R8me2s) by PRMT5, strongly repress gene expression [53–60]. Lately, it has been demonstrated that H3R2 is also symmetric dimethylated by PRMT5 and PRMT7, and presents in euchromatic regions in human cells, indicating that H3R2me2s is involved in gene activation [61, 62]. Lastly, Allis’s group has recently demonstrated, by MS analysis, the existence of H3R42me2a in human cells. Interestingly, this mark is decorated by PRMT4 and PRMT6 in vitro and in vivo, and stimulates transcription. It was proposed that this “nontail mark” facilitates a structural alteration in the chromatin, making it accessible for cellular process like transcription [63]. From the above, we can see that although the same PRMT is able to monomethylate and dimethylate multiple arginine residues of H3, the degree of methylation state on individual arginine residues is critical for dictating the ultimate functions (whether promoting or repressing transcription). It will be of great importance to delineate the control mechanism of PRMT and how such diverse functionality is achieved. Two novel arginine www.proteomics-journal.com

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methylation marks (H3R63me1 and H3R128me1) have been proven to be existed on human H3 in vivo by large-scale MS analyses, but the functions of these PTMs are currently unknown [64].

2.3 Citrullination Arginine residues can undergo not only methylation but also deimination, they are converted to citrulline after deiminated by a family of enzymes called “peptidyl arginine deiminases” (PADs), a process termed as “citrullination” [65]. But PADs are not true demethylases because they block methylation on arginine by converting it to citrulline. Furthermore, no enzyme has been identified that can convert citrulline back to arginine [66]. Kouzarides’s group first showed that PAD4 specifically deiminates residues R2, R8, R17, and R26 of the H3 tail in HEK293 and MCF-7 breast cancer cells [67]. This activity inhibits the methylation of these residues by PRMT4 thus causing transcriptional repression of target genes. And dimethylation of arginines can prevent deimination by PAD4 in which this conversion does not take place on dimethylated arginines [67]. Later, studies by Coonrod’s group, however, found that a unique subset of genes is disregulated following depletion of PAD2 from MCF-7 breast cancer cells. Subsequent chromatin immunoprecipitation (ChIP) analysis shows that PAD2 binds directly to these gene promoters and upregulates or downregulates expression of these genes via citrullination of H3R2, R8, and R17 [68]. Later on, using the same cell line, they further reported that citrullination of H3R26 is catalyzed by PAD2 and not by PAD4. Stimulation of estrogen receptor ␣ (ER␣) positive cells with 17␤-estradiol (E2) promotes global citrullination of H3R26 on chromatin. Moreover, by ChiP-sequencing (ChIP-seq) analysis, it was found that H3R26ci colocalizes with ER␣ at decondensed chromatin loci surrounding the estrogen-response elements of target promoters, suggesting that E2 stimulation induces the recruitment of PAD2 to target promoters by ER␣, whereby PAD2 then citrullinates H3R26, and leads to local chromatin decondensation and transcriptional activation [69]. From the above, we can see that PAD2 and PAD4 are both capable of citrullinating H3R2, R8, R17, and R26 in human cancer cells; however, whether the same phenomenon would occur in other normal cell types are uncertain. It is anticipated that future studies would address these unanswered questions.

2.4 Phosphorylation Another important PTM of histone is phosphorylation, which is written on serine, threonine, and tyrosine residues by various kinases such as aurora kinase (AURK), CHK, Janus kinase (JAK), and protein kinase C (PKC); while histone phosphorylation can be removed by phosphatases such as protein phosphatase 1 [70]. Histone phosphorylation has a sim C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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ilar role to acetylation in modulating nucleosome dynamics, which can promote the affinity of chromatin-binding proteins for their targets. Since the last decade, more and more phosphorylation sites were identified and their functions uncovered. Phosphorylation of histone H3 is special in that it associates on one hand with open chromatin during gene activation and marks on the other hand highly condensed chromatin during mitosis [71]. Phosphorylation of histone H3 creates together with acetylation and methylation marks at neighboring lysine residues as combinatorial patterns that are read by specific histone readers. Histone H3 phosphorylation is also involved in the activation of poised genes or by transient derepression of epigenetically silenced genes. It was proposed that histone H3 phosphorylation in the context with lysine methylation might temporarily relieve the silencing of specific genes without affecting the epigenetic memory [72]. For more detailed perspective of the related processes of histone phosphorylation, we highly recommend the reader to the following reviews [70, 71, 73]. In brief, phosphorylation of H3S10 and S28 were demonstrated to be associated with transcriptional activation of immediate early genes (such as c-jun, c-fos, and c-myc) by mitogenic and stress stimuli [71, 74]. Phosphorylation of H3S10 by AURKB is crucial for chromosome condensation and cell cycle progression during mitosis and meiosis. This modification mediates the dissociation of heterochromatin protein 1 (HP1) from heterochromatin and thereby facilitating chromosome condensation and/or segregation [75, 76]. The role of H3S10ph and S28ph in transcriptional activation is via the H3S10ph/H3S28ph and 14-3-3 protein–protein interactions, and the acetylation of adjacent residues (H3K9ac and H3K14ac) seem to promote the binding affinity of 14-3-3 protein to the dual phospho-acetyl mark [77, 78]. Later, phosphorylation of H3T3, T6, and T11 were also reported. During mitosis, phosphorylation of H3T3 by haspin helps to position “chromosomal passenger complex” at inner centromeres properly and modulates the activation of AURKB at centromeres to ensure accurate cell division [79–81]. It has been shown that H3T6 is phosphorylated by PKC␤I . H3T6 phosphorylation prevents demethylation of H3K4, thus maintaining the active methyl marks during androgendependent gene activation. Increased levels of PKC␤I and phosphorylated H3T6 positively correlate with high Gleason scores of prostate carcinomas [82]. Phosphorylation of H3T11 is catalyzed by several kinases including Dlk/Zip kinase, PKC-related kinase 1 (PRK1), and CHK1 [83–85]. Dlk/Zip kinase was reported to be involved in the phosphorylation of H3T11 during mitosis, and this modification predominantly concentrated at the centromeres, thus H3T11ph can be characterized as feature of mitotic chromosome [83]. PRK1 phosphorylates histone H3 at T11 on the promoter of androgen receptor target genes, phosphorylation of H3T11 by PRK1 accelerates demethylation of H3K9 and thus promotes gene activation [84]. CHK1 is a histone kinase that induces H3T11 phosphorylation in interphase, which regulates transcriptional repression in response to DNA damage [85]. www.proteomics-journal.com

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In 2005, Allis’s group discovered the existence of H3S31 phosphorylation by MS and biochemical methods and this modification is written uniquely on histone H3.3 variant. H3S31ph locates specifically to regions bordering centromeres in metaphase chromosomes during mitosis, yet, the kinase that phosphorylates H3S31 and the exact role of this PTM mark remains obscure [86]. Finally, there were some novel phosphorylation sites reported on human H3. Kouzarides’s group reported that H3Y41 is phosphorylated by JAK2 and this modification is linked to transcriptional regulation of JAK2-dependent genes. H3Y41ph was also demonstrated to exclude HP1␣ from binding to H3 and thereby relieving transcriptional repression of JAK2-dependent gene lmo2 [87]. Moreover, they recently used ChIP-seq analysis to define the genome-wide pattern of this modification. It was found that H3Y41ph marks active genes and locates at three different sites: (i) at a subset of active promoters, where it overlaps with H3K4me3, (ii) at distal cisregulatory elements, where it coincides with the binding of STAT5, and (iii) throughout the transcribed regions of active, tissue-specific hematopoietic genes [88]. Surprisingly, phosphorylation of H3T45 by PKC␦ is involved in neutrophils cell apoptosis in which it was proposed that this PTM induces structural change within the nucleosome to facilitate DNA nicking and/or fragmentation [89]. Lately, another kinase that catalyzes H3T45 phosphorylation is S6 kinase 2 (S6K2) and may play a role during cell proliferation and/or differentiation of leukemic cell lines U937, HL60, and THP1 [90]. Some novel histone phosphorylation marks have been proven to be existed on human H3 in vivo by MS and/or large-scale analyses, that is, H3T32ph, H3S57ph, H3T80ph, and H3T107ph, but the functions of these PTMs are still unclear [91–93].

2.5 ADP-ribosylation ADP-ribosylation is a type of protein PTM catalyzed by a group of enzymes named poly(ADP-ribose) polymerases (PARPs). The PARPs can hydrolyze nicotinamide adenine dinucleotide and transfer ADP-ribose to substrates. Two types of ADP-ribosylation exist including mono-ADP-ribosylation in which one unit of ADP-ribose is transferred to E/D/K residues of target proteins, and poly-ADP-ribosylation where multiple units of ADP-ribose are being added to target proteins [94, 95]. In human histone H3, the residues of K27 and K37 can undergo the modification of ADP-ribosylation, and this modification is mediated by PARP1. Since the attachment of ADP-ribose not only neutralizes the positive charge of the amino acid side chain, but instead reverses it into a negative charge, the functional consequences of ADP-ribosylation can be assumed to be even more drastic than those of other modifications [96]. It is suggested that ADP-ribosylation of histones may stimulate local chromatin relaxation to facilitate the repair process, indeed, histone ADP-ribosylation preceded DNA damage-induced histone H3 phosphorylation,  C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

suggesting that ADP-ribosylation of histone participates and plays an important role in DNA repair mechanisms [97].

2.6 Biotinylation There are two enzymes reported to promote biotinylation of histone lysine residues in human, namely biotinidase [98] and holocarboxylase synthetase (HCS) [99, 100]. Biotinidase belongs to the nitrilase superfamily of enzymes, and it works by hydrolytic cleavage of biocytin and then transfer the biotinyl residue to free amino groups in histones [98, 101], whereas HCS catalyzes the direct covalent binding of biotin to histones [100]. Histone biotinylation is a natural but rare modification, and less than 0.001% of human histones H3 and H4 are biotinylated, raising the questions that the abundance might be too low to elicit biological effects in vivo [101]. Zempleni’s group has essentially provided a number of interesting findings on histone biotinylation. By MS analysis, they showed that H3K4, K9, and K18 can undergo biotinylation; dimethylation of H3R2, R8, and R17 increased biotinylation of H3K4, K9, and K18, respectively, by biotinidase; while HCS interacts directly with histone H3 to mediate biotinylation of H3K9 and K18 [102, 103]. There were some speculated biological functions of biotinylation: first, evidences have shown that biotinylation of histones is related with cell proliferation in human cells [104]; second, biotinylation of histones may be involved with cellular DNA damage and cell apoptosis [105]; third, by conducting ChIP assays using novel biotinylation site-specific antibodies against H3K9bio and H3K18bio in human primary fibroblasts and Jurkat lymphoblastoma cells, results revealed that these marks were enriched in repeat regions such as pericentromeric alpha satellite repeats and long-terminal repeats while being depleted in transcriptionally active promoters in euchromatin. More importantly, the enrichment of H3K9bio and H3K18bio at genomic loci depended on the concentration of biotin in culture media at nutritionally relevant levels, suggesting a novel mechanism of gene regulation by biotin and that biotin deficiency could likely attribute to abnormal chromatin structures [106].

2.7 Acylation Acetylated lysine is the first acyl lysine modification discovered several decades ago. Recently, several new acyl lysine modifications that use immediates in metabolism have been proven to be existed on human H3 by MS-based proteomic analyses. These included formylation (fo), propionylation (pr), crotonylation (cr), and succinylation (succ), in which Zhao’s group has essentially identified many of the above novel acylation sites in histones [64, 107, 108]. Although further work is needed to interrogate the biological relevance of these histone lysine acylation marks, data from recent studies suggested that lysine acylation is a general means to facilitate www.proteomics-journal.com

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DNA access for processes such as transcription, replication, and repair.

2.7.1 Formylation Lysine formylation on histones is a secondary modification that arises from oxidative DNA damage, which is uniquely associated with histones and other nuclear proteins [109]. Through MS/MS analysis, it was shown that the lysine formylation sites occur at both the N-terminal tail and the globular domain of histone H3 (K18, K23, K56, K64, K79, and K122) [64, 110]. Lysine formylation in chromosomal proteins is relatively abundant and it often occurs at residues that can be methylated and acetylated, suggesting that this modification may interfere with the signaling functions of lysine acetylation and methylation. Therefore, formylation could potentially impact on chromatin function, and contribute to the pathophysiology of oxidative and nitrosative stress [109, 110].

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served PTM that presents in multiple species from yeast to human [64]. Despite the structural similarity between lysine crotonylation and lysine acetylation, they are substantially different. For example, altering the expression of HAT and HDAC had no effect on cellular histone crotonylation levels. These data suggest that the two types of PTMs are likely regulated by different modifying enzymes, and thus may be involved in distinctive cellular functions [64]. Through ChIPseq analysis, they also found that histone Kcr was enriched at either the active promoters or potential enhancers in both human somatic and mouse male germ cell genomes. Besides that, through exploring Kcr patterns during spermatogenesis in mice, the authors also revealed Kcr as a specific mark of active sex chromosome linked genes in postmeiotic male germ cells [64]. Yet, the enzymes that catalyze the formation and reversal of histone crotonylation mark are unknown, and the role of crotonylation that might play in histone structure and function is unknown too, which remains to be explored.

2.7.4 Succinylation 2.7.2 Propionylation In 2007, Zhao’s group confirmed that two well-known HATs, p300 and CREB-binding protein, could catalyze lysine propionylation in histone H4 peptides, establishing the first entry point that lysine propionylation is another novel histone PTM [111]. Later, they showed that propionylation also occurs in nonhistone proteins [112]. In 2009, they identified for the first time in yeast that H3K23 can be propionylated [107]. Later in 2009, through MS and Western blot analyses, Liu et al. detected the existence of propionylation on histone H3K23 in human leukemia U937 cells [113]. They demonstrated that HAT p300 can catalyze H3K23 propionylation, whereas HDAC SIRT1 can remove this mark, suggesting that histone propionylation might be generated by the same set of enzymes as for histone acetylation and that selection of donor molecules (propionyl-CoA or acetyl-CoA) may determine the difference of modifications [113]. Moreover, the level of propionylated K23 accounted for 7% in U937 cells, a level at least sixfold higher than in other leukemia cell lines or nonleukemia cell lines. During monocytic differentiation, the propionylation level in U937 cells decreased remarkably, indicating that this PTM is dynamically regulated. Given the fact that propionyl-CoA is an important intermediate in biosynthesis and energy production, H3K23pr may provide a novel epigenetic regulatory mark for cell metabolism [113].

2.7.3 Crotonylation Lysine crotonylation (Kcr) is a novel type of histone PTM identified by Zhao’s group using MS-based proteomic approach in the year of 2011 [64]. Six histone H3 lysine residues, that is, K4, K9, K18, K23, K27, and K56, can be crotonylated. It has been demonstrated that histone Kcr is an evolutionarily con C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Succinylation of lysine residue is also another novel type of histone PTM identified by Zhao’s group in the year of 2012. Using HPLC-MS/MS analysis and protein sequence alignment methods, they mapped the sites of this modification on histone H3, in which H3K14, K56, K79, and K122 can undergo this modification [108]. The level of succinylation is less abundant than that of histone lysine methylation and acetylation, which are the most abundant histone PTMs [108]. Additionally, most of the Ksucc sites are located in the globular domain and at the C-terminus of H3. Although the function of this PTM is not clearly understood, lysine succinylation induces more significant structural change than lysine acetylation by changing a positively charged residue to a negative one. Given the critical role of histone lysine PTMs in DNAtemplated processes, a dramatic structural change by lysine succinylation is likely to have significant consequences, thus lysine succinylation may play important roles in histone structure and function [108].

2.8 O-GlcNAcylation The modification of proteins by O-linked ␤-Nacetylglucosamine (O-GlcNAc) was first described more than 29 years ago [114]. The level of O-GlcNAcylation in cells are regulated by two evolutionarily conserved enzymes, a transferase [O-GlcNAc transferase (OGT)], and a hydrolase [O-GlcNAcase (OGA)], which adds or removes, respectively, O-GlcNAc on the target proteins [91, 115]. Lately, it was revealed that O-GlcNAcylation is also part of the histone code and the level of histone O-GlcNAcylation changes during mitosis and with heat shock [91]. Analogous to phosphorylation, histone O-GlcNAcylation is reversible and involved with cellular processes. Zhang www.proteomics-journal.com

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et al. first proposed that H3S10 is the major site of OGlcNAcylation (H3S28 as another potential O-GlcNAcylation site), since the expression of recombinant H3.3 harboring an S10A mutation abrogated histone H3 OGlcNAcylation relative to its wild-type counterpart [116]. Moreover, O-GlcNAcylated histones were lost from H3S10ph immunoprecipitates, whereas immunoprecipitation using antibodies against either H3K4me3 or H3K9me3 resulted in co-immunoprecipitation of O-GlcNAcylated histones, suggesting that H3S10glc somehow coexists with these active or inactive histone marks in chromatin, and potentially regulates chromatin conformation during transcription [116]. Later, through MS analysis, Fong et al. showed that H3T32 is a novel O-GlcNAcylation site. O-GlcNAc was detected at higher levels on H3 during interphase than mitosis, which inversely correlated with H3 phosphorylation [115]. And increased O-GlcNAcylations (H3S10glc, H3S28glc, and H3T32glc) were observed to reduce mitosis-specific phosphorylations at H3S10, S28, and T32. Moreover, inhibition of OGA prevented the mitosis-specific phosphorylations on H3, and also obstructed the G2 /M phase transition, indicating that histone H3 O-GlcNAcylation is another important mechanism that controls cell cycle transition [115]. In 2013, Deplus et al. reported some exciting findings about the interactions of OGT and TET (ten eleven translocation) enzymes in coordinating gene transcription [117]. TET, including TET1, TET2, and TET3, are enzymes that can convert 5-methylcytosine to 5-hydroxymethylcytosine (hmc) and provide a vital mechanism for subsequent DNA demethylation. Evidence has linked TET1 function to epigenetic repression complexes, while less is known about the roles of TET2/3 [118]. By unbiased affinity purification using HaloTag-TET fusion proteins to capture potential binding partners followed by LC/MS/MS proteomic identification of the binding proteins, it was shown that OGT is able to associate with TET2/3 [117]. OGT does not appear to influence the TET2/3 hmc activity, however, TET2/3 promotes OGT activity. Through ChIP-seq analysis, OGT and TET2/3 showed genome-wide colocalization, notably at CpG islands and at transcription start sites, and influence H3K4 trimethylation at active promoters in human cells. Moreover, they found that host cell factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific O-GlcNAcylation target of TET2/3-OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Reduction of either OGT or TET2/3 activity results in a direct decrease in H3K4me3 level as well as transcription [117]. Lastly, Zhang et al. also reported that TET2-OGT interaction is important for the chromatin association of OGT in vivo and promoting H2BS112 OGlcNAcylation and gene transcription [119]. The data from these studies uncovered a new paradigm in which double epigenetic modifications on both DNA and histones by the coordinated actions of TET-OGT, or with KMT, to regulate gene transcription.  C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

2.9 Glutathionylation Glutathionylation and oxidation of nuclear proteins appear as a reversible physiological mechanism to regulate DNA compaction, cell cycle, and DNA repair. The role of nuclear glutathione in cell physiology has become more important [120]. Recently, Lo Bello’s group showed that acquired drug resistance was suppressed in the doxorubicin-resistant breast cancer cell line MCF7/Dx after pretreatment with nitrosoglutathione (GSNO). The effect was accompanied by enhanced histone glutathionylation and accumulation of doxorubicin in the nucleus [121]. It was suggested that the increased cytotoxic effect of combined doxorubicin and GSNO treatment involves the increase of glutathionylation of histones, which alters the chromatin structure, and increases the exposure of potential nucleic acid binding sites to doxorubicin, thereby enhancing the cytotoxic efficacy of doxorubicin toward doxorubicin-resistant cells. Finally, they also proposed the cysteine 110 of histone H3 (H3C110) as a possible glutathionylation site [121]. Lately, it was confirmed by Pallard´o’s group by MS analysis that glutathionylation does occur in histone variants H3.2/H3.3 on their cysteine residue 110 [122]. It was suggested that histone H3 is able to sense cellular redox changes through glutathionylation of its cysteine, and this modification produces structural changes affecting nucleosomal stability, leading to a more open chromatin structure, which in turn, might assist replication; and this may explain why glutathionylation of H3 is increased in fast proliferating cancer cells but decreased in aging cells [122]. The data from these studies point out a new role for nuclear GSH in the regulation of chromatin structure, yet, more experiments should be done in order to have a better understanding of this PTM mark, such as its abundance and distribution within the genome.

2.10 Ubiquitylation Ubiquitylation is a fairly large PTM (each ubiquityl group is 8.5 kDa) on protein in which the C-terminal end of ubiquitin is covalently attached to the epsilon amino group of the lysine residue of target protein, either as a single entity or as chains [123]. Polyubiquitin chains have different structure and regulatory functions depending on the ubiquitin residues they are linked (e.g., whether through K48 or K63 linkage) [124]. Ubiquitylation generally targets proteins for proteasomal degradation, but in case of histones it provides other signals important for gene regulation. Histone ubiquitylation is catalyzed by a group of ligases named lysine ubiquitinases and removed by deubiquitinases [125]. Although there is evidence that H3 can be ubiquitylated in response to DNA damage, yet, the exact ubiquitylation sites have not been delineated [126]. However, data from large-scale ubiquitinmodifed proteome analyses have shown that indeed multiple lysines of H3 (K14, K18, K23, K27, K56, K79, and K122) can be ubiquitylated [127–130], but it is still unclear about their www.proteomics-journal.com

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functions and whether these decorations are related to DNA damage. Previous studies have shown that “ubiquitin-like with plant homeodomain and ring finger domains 1 (short name as Uhrf1),” a ubiquitin ligase that specifically binds to hemimethylated DNA and has an essential role in maintenance of DNA methylation by recruiting DNA (cytosine-5)methyltransferase 1 (Dnmt1) to hemimethylated DNA sites [131, 132]. In addition, Uhrf1 has been shown to bind to H3K9me3 marks and promote local chromatin ubiquitylation, for proper heterochromatin formation in mammalian cells [133]. In 2013, Nakanishi’s group provided the mechanistic link between DNA methylation and DNA replication through H3K23 ubiquitylation [134]. They showed that Dnmt1 depletion results in a marked accumulation of Uhrf1dependent ubiquitylation of H3K23. Moreover, the ring finger mutant of Uhrf1 fails to recruit Dnmt1 to DNA replication sites and maintain DNA methylation in mammalian cells [134]. Their interesting findings strongly suggest that Uhrf1dependent ubiquitylation of H3K23 acts as a platform for the recruitment of Dnmt1 to DNA replication sites, for faithful propagation of DNA methylation patterns during DNA replication.

3

Perspectives

It should be noted that as more and more PTMs are identified on histones, the ultimate function of many of these PTMs still require further intensive study. Therefore, we hope the reader would find the information here useful as a reference point. So far, histone H3 possesses the most number and diversity of PTMs. Significant progress has been made in recent years regarding how histones are modified, how these marks are being read by binding or effector proteins, and how such cross-talk interpreted into cellular processes. Altogether, these recent investigations are shedding light on the molecular basis of histone PTMs. Since histones are nucleoproteins that closely linked to the cellular physiological processes, deciphering the distinctive patterns of these histone PTMs are the key to the understanding of epigenetic regulation of diverse biological processes. Increasing our knowledge to the relationship of histone PTMs and the associated functions might hopefully give us clue to search for novel therapy for human diseases and cancers. High-resolution MS analysis has become an indispensable tool for the identification and assignment of PTMs due to its high speed and sensitivity. Although novel histone PTMs have been validated to be existed in vivo by this method, some of them have not yet been functionally characterized. Taken the diversity of histone PTMs into consideration, it will be a challenging task to identify all the possible PTMs on histones and their specific biological effects. Moreover, it should be noted that the effects of these PTM marks could be context-dependent such that one PTM can affect the modification/function of other/neighboring PTMs. Therefore, it is  C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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deemed necessary to examine the global histone PTM profile in order to have a better understanding of this language. In conclusion, this review is only a brief summary of the complex realm of histone H3 PTMs and the associated functions, and the past and future research findings in this area would hopefully enable us to decipher the histone code and ultimately shape the epigenetic landscape. Due to space constraints, it has been necessary to cite recent articles wherever possible; our sincere apologies to the hundreds of authors whose primary contributions are therefore not listed. This work was supported by National Natural Science Foundation of China Grants 31170785 and 81101785 (A.T.Y.L.), Fund for University Talents of Guangdong Province (A.T.Y.L.), and Guangdong Natural Science Foundation of China Grant S2012030006289. We would like to thank members of the Lau and Xu laboratory for critical reading of this review. The authors have declared no conflict of interest.

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Posttranslational modifications of human histone H3: an update.

Histone proteins, the fundamental components of chromatin, are highly conserved proteins that present in eukaryotic nuclei. They organize genomic DNA ...
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