Briefings in Functional Genomics and Proteomics

Briefings in Functional Genomics and Proteomics 2006 5(3):190-208; doi:10.1093/bfgp/ell032

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Special Issue Papers

Simple histone acetylation plays a complex role in the regulation of gene expression

Hiroki Fukuda, Norihiko Sano, Shinsuke Muto and Masami Horikoshi

Corresponding author. Masami Horikoshi, Laboratory of Developmental Biology, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Tel: +49 (3) 5841 8469; Fax: +49 (3) 5841 8468; E-mail: horikosh{at}iam.u-tokyo.ac.jp

	ABSTRACT

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Eukaryotic DNA is packaged into chromatin by histone proteins, which assemble the DNA into an organized, higher-order structure. The precise organization of chromatin is essential for faithful execution of DNA-mediated reactions such as transcription, DNA replication, DNA repair and DNA recombination. The organization of chromatin is considered to be regulated by a variety of post-translational modifications of histones, such as acetylation, methylation, phosphorylation, ubiquitination, SUMOylation and poly-ADP-ribosylation. The relationship between histone acetylation and gene expression was first observed in 1964. Since then, a great deal of evidence has accumulated showing that not only transcription but other DNA-mediated reactions also are regulated by histone acetylation. With regard to the putative mechanism(s) by which histone acetylation regulates the flow of genetic information, site-specific modification and recognition of acetylated histone/DNA complexes have been postulated. Elucidation of the downstream effects of histone modification, as well as the identification, isolation and characterization of the relevant factors involved, have aided in our understanding of the mechanisms of regulation of DNA activity by histones. Currently, state-of-the-art technologies that enable genome-wide analysis are allowing insight into a critical and interesting question in eukaryotic transcription: are the principles that govern transcription of individual gene loci applicable to the genome as a whole? Here, we review the recent progress on histone modifications, with an emphasis on the role of histone acetylation in gene expression.

Keywords: histone acetylation, transcription, chromatin

	BEFORE THE DISCOVERY OF HISTONE ACETYLTRANSFERASE

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In eukaryotes, genomic DNA is packaged with core histones into nucleosomes [1–3], which are in turn packaged into highly compacted chromatin by additional chromatin-modulating factors. Chromatin structure regulates the access of factors that control DNA-mediated reactions like transcription, DNA replication and DNA repair, to specific regions of DNA. Post-translational modifications of histones, such as acetylation, methylation, phosphorylation, ubiquitination, SUMOylation and poly-ADP-ribosylation, are now known to be some of the mechanisms that regulate chromatin structure and function [4–6]. While the enzymes involved in catalysing these modification reactions have been the subject of vigorous study in the last decade, the pioneering work in this field, establishing a close relationship between histone acetylation and active gene expression, was done by Allfrey et al. [7] in 1964.

From 1964 to 1996, research on transcriptional regulation of gene expression was rarely done at the chromatin level, but focused mainly on transcription of naked DNA that was not in complex with histones. These studies enabled researchers to identify and characterize a host of eukaryotic transcription factors that comprise the transcriptional machinery, such as RNA polymerase [8], general transcription factors [9, 10] and a variety of sequence-specific DNA binding proteins (DBPs). In the latter part of this period, a number of transcriptional coactivators (e.g. GCN5 [11] and p300/CBP [12–14]) were also isolated and characterized [15, 16]. These coactivators stimulate transcription by enhancing the functional association of DBPs to the basal transcriptional machinery. However, their structural/mechanical roles, biochemical activities and overall significance in transcriptional regulation remained unclear.

Paralleling these studies on transcriptional regulation of naked DNA, there was considerable progress on the biochemical and genetic characterizations of chromatin structure and function. In 1974, Kornberg [1] demonstrated the existence of nucleosomes, and later, several researchers elucidated roles of histones as repressors [17–21]. In the 1980s, Grunstein's group [22] demonstrated that the histone tail was involved in the regulation of gene silencing and that acetylation of histone H4 was essential for gene activation [23]. However, while the relationship between histone acetylation and transcriptional activity was becoming evident, the underlying molecular mechanism was as yet undetermined, because little was known about the enzymes that catalysed acetylation of histones. Identification of these enzymes then became a major step of research.

	AFTER THE DISCOVERY OF HISTONE ACETYLTRANSFERASE

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In 1995, the first histone acetyltransferases (HATs) were identified. Sternglantz's group [24] isolated HAT1, a cytosolic HAT encoded by yeast, using a genetic approach, and Allis' group [25] demonstrated HAT activity in a single polypeptide of 55 kDa (p55) in macronuclear extracts of Tetrahymena thermophilia. The following year, the cloning and sequencing of p55 revealed that it had a striking similarity to the yeast transcriptional coactivator Gcn5 [26]. This observation was both unexpected and striking, and represented a breakthrough in the marriage of chromatin study and transcriptional regulation. Subsequently, various transcriptional coactivators or subunits of the basal transcriptional machinery were found to possess HAT activity, and many HATs were found to form multisubunit complexes [27–30].

On the basis of sequence homology, each HAT falls into one of three categories: the Gcn5-related N-acetyltransferase (GNAT) family; the MOZ, Ybf2/Sas3, Sas2 and Tip60 (MYST) family; and others (Table 1). GNAT family members consist of HATs that have sequence and structural similarity to Gcn5 [60, 61], and regulate the recruitment of transcription factors to their target promoters [62]. In contrast, MYST family members are involved in the regulation of a variety of DNA-mediated reactions, such as promoter-driven transcriptional regulation [63], long-range/chromosome-wide gene regulation [64, 65], double-stranded DNA break repair [66, 67] and licensing of DNA replication [68]. Other HATs include p300/CBP, which has broad substrate specificity for histones and is a ubiquitous regulator of gene transcription; CCG1 (TAF_II250/TAF1), which is a subunit of the general transcription initiation factor TFIID and nuclear hormone-regulated HATs such as SRC1 and ACTR (SRC3). Although p300/CBP has been extensively characterized, less is known about TAF_II250, SRC1 and ACTR. Most HAT studies now combine structural and functional analyses, and involve other chromatin-related factors/enzymes, such as ATP-dependant chromatin-remodelling enzymes and ATP-independent histone chaperones.

View this table: [in this window] [in a new window]   Table 1: A list of identified histone acetyltransferases

 
Acetylated lysine residues are deacetylated by a specific class of enzymes called histone deacetylases (HDACs). In the year the first HAT was identified as transcriptional coactivator, Schreiber's group [69] purified and cloned human HDAC1, using an affinity matrix of trapoxin, an HDAC inhibitor. Sequence analysis of HDAC1 revealed that its primary sequence was similar to that of the yeast transcriptional corepressor Rpd3, which was subsequently found to possess HDAC activity also. According to phylogenetic analysis, HDACs can be divided into four major classes [70] (Table 2). Class I displays sequence homology to yeast Rpd3, which deacetylates all four core histones, and is ubiquitously expressed in human cells. Class II HDACs are similar to yeast Hda1, which deacetylates histones H2B and H3 [105], and is expressed in a tissue-specific manner [106]. The activities of the members of classes I and II are zinc-dependent. Classes III HDACs are NAD-dependent, and are related to yeast Sir2, which is involved in the regulation of gene silencing and aging [107]. Class IV consists of the newly identified HDAC11, which is also zinc-dependent [70, 104]. Through identification and characterization of HATs and HDACs, we have learned that these two families of enzymes with opposing activities regulate a variety of nuclear reactions. The key steps next involve identifying the mechanisms of coordination of these enzymes in different processes.

View this table: [in this window] [in a new window]   Table 2: A list of identified histone deacetylases

 

	HISTONE AND SITE-SPECIFICITY OF HATS

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A variety of HATs have been isolated and characterized. Collectively, these proteins are involved in almost all nuclear reactions, including transcription, DNA replication, DNA repair and so on (Table 1). The involvement of HATs in multiple processes seems to partially depend on their substrate specificity. Several models have been proposed for the molecular basis of HAT specificity. One of the models invokes the primary sequence in the vicinity of the target acetylated lysine residue. In this model, every lysine residue belongs to one of three classes and six groups (Figure 1A and B). Classes are defined by the chemical properties of the amino acid residues located amino-terminal to the acetylated lysine, i.e. glycine or alanine for class I, serine or threonine for class II and lysine or arginine for class III. Each class is further divided into two groups on the basis of similarities in flanking amino acid sequences. The correlation between classification and corresponding type of HAT is indicated in Figure 1B [108].

View larger version (35K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1: Substrate specificity of HAT: ‘two-step classification’ and ‘Allocation’ models. (A) Acetylation sites are shown in circle, along with surrounding residues in the primary amino sequence of human histone tails. Acetylation of most of these lysines have been verified using specific antibodies. Recent proteomic analysis has revealed four additional acetylation sites in the N-terminal tails. (B) Two-step classification hypothesis. Lysines acetylated in vivo can be classified into three classes (class I–III) and six groups (groups A–F) on the basis of the primary sequence in the vicinity of the acetylated lysine. (C) Allocation of lysine specificities among members of the MYST family of HATs. (Left) Six lysines (in free histones) are acetylated by the MYST-HAT domain. (Right) Lysines acetylated in vivo by MYST family HATs. (D) Two-step classification hypothesis and allocation strategy to select specific lysines by HAT. (Left) The potential specificity of each enzyme is defined by catalytic domain structures, which correspond to the two step classification of lysines. (Right) Lysine specificity is allocated by family members, and each member regulates specific lysine(s) in vivo.

 
Another model proposes that the combination of subunits in the HAT complex dictates substrate specificity. The formation of a multisubunit complex is required for HATs to acetylate histones in the context of the nucleosome. In some cases, the specificity of HAT complexes for nucleosomal histones is more stringent than for the catalytic subunits alone against free histone. The followings are some examples from the MYST family of HATs. In budding yeast, the MYST family consists of Esa1, Sas2 and Sas3. Although, individually they could acetylate six class I lysine residues (H2A-K5, H3-K14, H4-K5/8/12/16), multisubunit complexes containing Esa1, Sas2 and Sas3 acetylate H2A-K5 and H4-K5/8/12, H4-K16 and H3-K14, respectively (Figure 1C). Thus, the formation of HAT-containing complexes appears to narrow the substrate specificity of each member of the MYST family in budding yeast. This mechanism for restricting substrate specificity is named ‘Allocation’ [30] (Figure 1D).

Tertiary structure analysis provides insight into the mode of specific recognition of substrates by HAT proteins. The three-dimensional (3-D) crystal structures of Gcn5/PCAF [109–111], Esa1 [112] and Hat1 [113] revealed that these HATs have a structurally conserved central core domain and more divergent N- and C-terminal domains. The central core domain plays a particularly important role in histone substrate catalysis, while the N- and C-terminal domains are important in histone substrate binding. The structural basis for the interaction between HATs and their substrates during the histone modification reaction has also been examined using 3-D structural analysis. The structures of a Gcn5/CoA/histone H3 peptide (unphosphorylated) complex and a Gcn5/CoA/histone H3 peptide (phosphorylated at Ser10) complex revealed a mechanism by which phosphorylation of histone H3 Ser10 enhances acetylation of histone H3 Lys14 by Gcn5. Phosphorylated histone H3 undergoes a significant structural rearrangement, which promotes a stronger interaction between Gcn5 and histone H3 [114]. Further structural analysis of complexes like the two just described will validate and complement models based on biochemistry or genetics, and lead to a better understanding of the molecular basis of HAT substrate specificity.

HAT also acetylates non-histone proteins. Since the first report of p53 as a non-histone target of p300/CBP [115], the list of HAT targets has expanded rapidly [116, 117]. Transcription factors occupy a large portion of the list, which also includes cytoskeletal proteins, nuclear receptors, nuclear import proteins and many others. Similar to histones, acetylation of these proteins regulates their function: i.e. modulates DNA-binding activity or protein polymerization, or inhibits ubiquitination. The fact that acetylation exists in organisms as old as archaea is an evidence of its evolutionary conservation, and highlights its importance as a mechanism for modulating protein function [118].

	SPECIFIC RECOGNITION OF ACETYLATED RESIDUES BY VARIOUS PROTEIN INTERACTION DOMAINS

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In recent years, the use of methods like mass spectroscopy has revealed that many lysines of histones are acetylated [119–126]. Based on analysis using histone point mutants or antibodies that recognize specific acetylated residues, several biochemical and biological reactions have been linked to specific patterns of histone acetylation (Table 3).

View this table: [in this window] [in a new window]   Table 3: Examples of residue-specific acetylation of histone and their downstream reactions

 
The proteins that interact with histones in an acetylation-dependent manner are recruited to specific acetylated residues. This recruitment then triggers subsequent reactions involving chromatin. Structural domains which specifically recognize acetylated histones have been identified. The bromodomain of HATs Gcn5, PCAF, CCG1 and CBP recognizes specific acetyllysine residues in histones, HIV Tat, p53, c-Myb and MyoD (Table 4). Bromodomains are found in many chromatin-associated proteins and HATs. The association of bromodomains and acetylated histones stabilizes the acetylation state and/or regulates the activities of bromodomain-containing chromatin factors.

View this table: [in this window] [in a new window]   Table 4: Summary of bromodomain with known acetyllysine-binding activity

 
The chromatin-remodelling complex SWI/SNF, which includes the bromodomain-containing protein BRG1, is recruited to promoters through the interaction between the bromodomain of BRG1 and CBP-acetylated H4 Lys8 [142]. In a similar manner, the bromodomain of TIP5, the large subunit of NoRC (an SNF2h-containing chromatin-remodelling complex), interacts with acetylated histone H4 Lys16, and cooperates with an adjacent PHD finger to recruit HDAC and DNA methyltransferase to rDNA [127]. Other domains, such as the chromodomain and WD40 domain, have been shown to specifically recognize modified histones [147]. Detailed analyses of the relationship between those domains and histone acetylation will help elucidate the patterns of modification/interaction that regulate the function of histones and other related factors.

	INFLUENCE OF HISTONE MODIFICATION TO SUBSEQUENT REACTIONS

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Structurally, the chromosome is a simple array of nucleosomes and DNA. Temporal and spatial regulations of DNA-mediated reactions is achieved by introducing increasingly complex patterns of variation in the nucleosome and/or DNA, such as DNA methylation, covalent modifications of histones and the use of histone variants. Histone modifications have been a primary target of study because the different combinations and patterns of modifications can potentially help explain the vast structural and functional diversity of chromosomes.

Models for how the variations in histone modification influence chromosomal function can be divided into two groups based on the role of the histone-binding domain (HBD), which recognizes specific patterns of histone modifications (as described in the section ‘specific recognition of acetylated residues by various protein interaction domains’). Models that invoke a role for the HBD are based on the histone code hypothesis [5] (Figure 2A) and variations thereof [147, 149, 150], while the alternative model is termed the direct interaction model. The former postulates that particular patterns of histone modification act as a signal to other proteins with HBDs, which then bind to histones in a modification-specific manner. Chromatin-related factors are then recruited to the modified histone. For instance, when histone H2A-S129 is phosphorylated by Mec1 during double-stranded DNA cleavage [151], HAT NuA4 is recruited to its specific target lysine via recognition of phosphorylated H2A-S129P by the NuA4 subunit Arp4 [152]. NuA4 subsequently acetylates histone H4. The mechanisms for sequential modification and regulation of chromatin function are very similar to those that have been proposed for cellular signal transduction [153].

View larger version (32K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 2: Models for triggering downstream effects of histone modification. (A) The histone code. Phosphorylation of H2A-S129 induces acetylation of H4 through recruitment of NuA4. (B) Binary switches model. Phosphorylation of H3-S10 inhibits recognition of methylated H3-K9 by HP1. (C) Multinucleosome code model. Domain Z integrates histone modification states on separate nucleosome through binding domains X and Y, and delineates the border between hyperacetylated and hypoacetylated regions. (D) Proposed mechanism for nucleosome mobility regulation. Modification of residues on the lateral surface of the nucleosome interferes with the histone-DNA interaction, and alters the mobility of nucleosomes on DNA. (E) Interaction between the histone H4 tail and the acidic patch on an adjacent nucleosome. Amino acids 14–17 of H4 have been shown to mediate nucleosome compaction [148].

 
There are three advanced versions of the histone code hypothesis, termed binary switches, multinucleosome code and molecular barcode. The binary switches model expands the traditional idea that a recognition domain recognizes one modified residue, and presents the possibility that histone binding is further mediated by combinations of modification states in distinct residues (Figure 2B) [149]. This model is supported by results showing that phosphorylation of histone H3-S10 resulted in dissociation of the complex of HP1 and methylated H3-K9 [154, 155]. These results indicated that HP1 recognition is dependent on the modification state of both H3-S10 and H3-K9. The multinucleosome code theory proposes that the functional effects of histone modification occur on not one nucleosome, but on multiple, separate nucleosomes [150]. This hypothesis implies that there are mechanisms for recognizing histone modification patterns in the context of the entire chromosome (e.g. recognition of nucleosomes positioned at the boundary between hyper- and hypo-acetylated regions) (Figure 2C). This model, however, remains to be experimentally verified. Finally, the molecular barcode model applies the principles of the histone code hypothesis to non-histone proteins, such as p53 [147]. It too is still under experimental investigation. As suggested by these models, the functional outcome of histone modification could be achieved by diversifying the recognition domains used to interact with modification residues, and/or adding non-histone proteins to the repertoire of modification targets.

In the direct interaction model, histone modification directly regulates (i) intra- and (ii) inter-nucleosomal interactions without the involvement of specific recognition domains. Intra-nucleosomal refers to histone–DNA interactions. This aspect of the model proposes that modification of amino acid residues at the histone–DNA interface in the nucleosome core alters the ability of DNA to interact with histones, and subsequently alters nucleosome mobility on the DNA (Figure 2D) [156]. Support for this model was provided by the observation that modification sites identified by mass spectrometry map primarily to the lateral surface of the nucleosome, which is potentially involved in mediating histone–DNA interactions. Inter-nucleosomal refers to interactions between nucleosomes. The X-ray crystal structure of the nucleosome indicates that the tail of histone H4 interacts with an acidic patch on the H2A/H2B dimer of an adjacent nucleosome (Figure 2E) [3]. The significance of this interaction has been bolstered by a variety of biochemical and genetic experiments. For example, nucleosomes are unable to form higher order chromatin structure when they contain histone H4 that is acetylated at K16 [157].

All of these models are based on the concept that a pattern of histone modification determines what reactions should occur next. Supposing that the number of acetylation sites on a histone is ‘n’, the number of possible modification patterns, if the sites can be either acetylated or deacetylated, should be ‘2ⁿ’. However, this number does not seem to accurately reflect acetylation in vivo. Histone H4 has four candidate lysines for acetylation (K5, K8, K12 and K16), therefore, the number of possible modification patterns should be 16 (=2⁴). It has been reported, however, that gene expression patterns of mutant strains which hold mutation in these four lysines are classified into only eight transcriptional states [158]. This numerical discrepancy between potential combinations and real patterns of gene expression is most likely due to redundant functions of K5, K8 and K12. Because transcriptional regulation by histone H4 acetylation involves several reaction steps, it is not clear whether the acetylation states of lysines K5, K8 and K12 are redundant, i.e. trigger the same reaction. These observations raise the issue of the downstream effectors of histone modification. Regrettably, this question is not fully answered, and it remains one of the critical gaps in our understanding of the concert of simplicity and complexity behind histone modifications and subsequent nuclear reactions.

	TRANSCRIPTIONAL REGULATION BY ACETYLATION AND DEACETYLATION

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Transcriptional regulation in eukaryotes is a complex multistep process. It involves binding of DBPs to specific DNA sequence elements in a spatially and temporally restricted manner and subsequent remodelling of chromatin at enhancer and promoter loci, as well as other modulatory regions, by a variety of chromatin factors and enzymes. A critical component of chromatin remodelling is the regulation of histone acetylation/deacetylation by HATs and HDACs. These enzymes are recruited to active transcription sites by various types of transcription or chromatin factors, and in turn regulate the recruitment of additional factors by acetylating or deacetylating histones in a specific manner. For example, acetylation of histone H4-K8 and histone H3-K9/K14 plays a pivotal role in the recruitment of the SWI/SHF chromatin-remodelling complex and the general transcription initiation factor TFIID, respectively, during transcription initiation [142].

Kadosh and Struhl [159] proposed a mechanism for transcriptional regulation by histone acetylation at promoters, showing that the DNA-binding protein UME6 recruits HDAC Rpd3 to the INO1 promoter and represses transcription by histone deacetylation. Transcriptional activation triggered by targeting of HATs to promoters has now been reported for many genes. For example, it has been shown that the DNA-binding protein Gcn4 targets HAT Gcn5 to the HIS3 promoter [160]. However, nucleosome acetylation is controlled by factors other than recruitment of HATs and HDACs to promoters by DBPs. Accumulating evidence suggests that regulation of acetylation is also achieved by inhibition of HAT activity by histone variants like H2A.Z [161] and macroH2A [162], or by recruitment of HATs by pre-mRNA [163]. Further studies on the regulation of HAT and HDAC activities will provide a comprehensive description of the diverse regulatory mechanisms for histone acetylation and deacetylation on gene activities.

The promoter regions of actively transcribed genes are highly acetylated. However, the coding regions of genes harbour a low level of acetylation [164, 165], presumably to suppress transcriptional initiation from cryptic intragenic, promoter-like sequences (Figure 3) [166, 167]. These observations indicate that there are boundaries between hyper- and hypo-acetylated regions within a gene. Interestingly, mutation of HAT and HDAC not only shifts the border between functional regions of chromosomes (described later in chapter VII), but also alters the division between functional regions within a gene. For example, in the conditional knockout of Esa1, which is the catalytic subunit of the NuA4 HAT complex, histone deacetylation activity at promoters is augmented, and transcription is repressed [168]. On the other hand, deletion of the subunit of the Rpd3 HDAC complex that is involved in histone deacetylation increases histone acetylation and transcriptional initiation from the 3' region of the Open Reading Frame [166]. Thus, acetylation and deacetylation of histones themselves, along with their position within a gene, appear to be highly regulated.

View larger version (30K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 3: Regulation of histone acetylation levels in promoter and coding regions. Promoter regions are hyperacetylated by NuA4, whereas coding regions are hypoacetylated by Rpd3(S). Hypoacetylation represses intragenic transcription initiation.

 
Surprisingly, although the histone acetylation state of a promoter is opposite that of its corresponding coding region, regulation of acetylation/deacetylation in both regions seems to be achieved by SET2 [166, 169, 170]. SET2 mediates histone H3 methylation at K36 (Figure 3). The Eaf3 chromodomain interacts with mono-, di- or tri-methylated H3-K36 peptides, and with tri-methylated histone H3-K4 [166, 167]. In light of the fact that Eaf3 is a component of the HAT NuA4 and HDAC Rpd3 complexes [166, 170], the mechanism for controlling the pattern of histone acetylation in promoter and coding regions of a particular gene could involve recognition of methylated H3-K4 or K36 by Eaf3. Additional studies are needed to understand how the same modification recruits functionally opposed complexes such as HATs and HDACs. Other histone modifications and/or DBPs may be instrumental in determining the specificity of chromatin-regulatory enzyme complexes that are recruited at a given time and place.

	REGULATION OF LONG-RANGE/CHROMOSOME-WIDE GENE EXPRESSION

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The regulation of long-range, or chromosome-wide, gene expression involves higher-order chromatin organization compared with expression of a specific gene. Since the discovery of position effect variegation (PEV) in Drosophilla melanogaster by Muller and Mott-Smith in 1930 [171], long-range chromosomal gene regulation, including the establishment and maintenance of transcriptionally active or inactive regions, has been studied at several gene loci in other species. In yeast, studies have examined telomere proximal regions, cryptic mating loci, centromeres and rDNA loci, and in higher eukaryotes, the ß-globin gene locus, HOX gene cluster and the X chromosome are well-characterized [172–179]. Models based on the results of these studies propose that not only specific DNA elements, but also histone modifications, including acetylation, contribute to chromosome-wide gene regulation. Recently, genome-wide chromatin immunoprecipitation (ChIP) analysis revealed that localization of acetylated and/or methylated histones is broadly maintained at coding regions of multiple genes, as well as promoter regions [180, 181].

A boundary DNA element, termed an insulator, is believed to function as stable ‘wall’, which actively restricts the function of transcriptional enhancers or silencers to distinct regions on the chromosome [179]. According to this theory, the positions of borders are defined first and distinct functional regions are determined as a result (Figure 4). An alternative model proposes that hyper- and hypo-acetylated chromosomal regions are established by the balance of opposing enzymatic activities of HATs and HDACs, and the chromosomal gradient of histone modification acts as a border between transcriptionally active and inactive regions [35, 36, 182]. That is, the positions of distinct functional regions are defined first and the borders are passively determined according to the enzymatic balance. These two models, the former fixed border and the latter negotiable border, are not mutually exclusive. Which mechanism is utilized likely depends on various spatial and temporal conditions in the nucleus. To establish a negotiable border, histone (or DNA) modification enzymes must be recruited to specific regions on chromosomes. The most straightforward mechanism for doing so would involve specific DNA elements interacting directly or indirectly with these enzymes. Previously established boundary elements could also be involved in establishing a negotiable border. In a recent study it was shown that a boundary element also recruited HAT [183]. In this case, the recruited enzymes modified histones that were adjacent to the border element. Thus, the border established by negotiation was close to an existing boundary element. In this case, these elements can be recognized as fixed borders that help form a negotiable border.

View larger version (44K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 4: Negotiable border and fixed border models. (A) Chromosomal gradient of histone acetylation near telomeres. Regions near the telomere end are hypoacetylated at H4-K16 through the HDAC activity of Sir2, whereas telomere-distal regions are hyperacetylated through the HAT activity of Sas2. (B) Models for establishing borders on chromosome. (Left) Fixed border model. An ‘insulator’ DNA element (gray box) recruits factors (gray circles) that function as a barrier and/or an enhancer blocker. (Right) Negotiable border model. Enzymes with opposing activities are recruited to specific DNA elements by factors bound to the DNA. Modifications define chromosome states and establish a border somewhere between the two DNA elements. (C) Non-biological examples for fixed borders (left: the Great Wall of China and the Berlin Wall) and negotiable borders (right: American Civil War and Battle of Sekigahara) [30, 182]. In the former set of examples, the positions of these two walls were fixed, and defined the territories of two countries. In the latter, the territories were defined by jostling and shoving of the two armies, and the borders changed during the war.

 
Numerous studies have helped elucidate how chemical information in the form of chromosomal histone modifications is transmitted to downstream effectors. Some proteins have domains, like the bromodomain and chromodomain, which specifically interact with modified histones. For example, the interaction between acetylated histone residues and the bromodomain-containing protein Bdf1 at telomere-distal regions stabilizes histone acetylation, and contributes to the anti-silencing status of genes in those regions [145]. In this way, we now have an understanding of the events that regulate the establishment and maintenance of gene silencing and anti-silencing, yet this information represents just half of the entire picture.

Several approaches have been developed that enable us to examine high-order structural reorganization within a chromosome or between two interacting chromosomes. Through conventional imaging techniques like fluorescence in situ hybridization (FISH), we know where active and inactive genes are positioned within the nucleus [184]. A more advanced technology, called chromosome conformation capture (3C), allows us to measure the proximity between two chromosomal regions, and analyse long-range inter- and intra-chromosomal regulatory interactions [185]. The results of this type of analysis show that there is a correlation between the location of a chromosome in the nucleus and gene activation.

The identification and characterization of histone modification enzymes other than HATs and HDACs that regulate long-range gene expression are now underway. These studies have accelerated in recent years with the ability to analyse chromosome-wide gene expression and diverse sets of histone modifications. We are now able to focus on the association between these other enzymes, and sequence-specific DBPs, which determine the gene locus for activation or inactivation. This type of approach will enable us to elucidate a comprehensive, diverse set of principles for the regulation of gene and chromosome function by histone modification.

	GENOME-WIDE ANALYSES OF HISTONE ACETYLATION

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The availability of complete genomic sequences of a number of organisms and of high-throughput technologies currently allows us to analyse the functional roles of histone modifications on a genome-wide scale [186]. Two technologies in particular have enabled us to expand the scope of analysis from specific DNA regions to whole chromosomes: ChIP on CHIP [187], which is a sequential analysis by ChIP and DNA microarray, and genome-wide mapping technique (GMAT) [188], a combination of ChIP and serial analysis of gene expression technology (SAGE). Use of these technologies will facilitate our general understanding of the relationship between various gene activities and the regulation of histone modification.

Genome-wide analyses of histone modification patterns have revealed that there is a correlation between histone acetylation status and transcriptional activity [189–191]. Using recently developed microarray technologies, such as the high-resolution oligonucleotide tiling array, we can analyse histone modification patterns in great detail. What follows is a summary of results from several genome-wide analyses of histone acetylation in model organisms. In budding yeast, ChIP on CHIP analysis revealed a correlation between transcriptional activity and acetylation of histones H3 and H4, and trimethylation of histone H3 Lys4 in promoter regions and dimethylation of histone H3 Lys4 in coding regions [164, 192, 193]. Analysis of genome-wide occupancy by histone modification enzymes suggested that HATs and HDACs are recruited to the promoters of active genes [194]. On the other hand, analysis using GMAT showed that the highest levels of acetylation are in the 5' coding region of a gene, not in the promoter [188]. In fission yeast, ChIP on CHIP analysis revealed that acetylation of histones H3 and H4 and dimethylation of histone H3 Lys4 were generally enriched in intergenic regions, peaking in the vicinity of the ATG codon, then sharply decreasing about 500 bp into the coding region and maintained at a reduced level thereafter. The histone acetylation patterns correlate to gene expression levels but not on gene length [165, 195]. In higher eukaryotes, including fruit fly, mouse and human, both ChIP on CHIP and GMAT analyses showed that histone acetylation occurs at the 5' end of active genes [180, 181, 196–198]. Through these types of analyses, common histone acetylation patterns among all species have been documented.

The role of histone modification enzymes has also been examined at a genome-wide level. Microarray analysis of budding and fission yeast in which specific HDACs were disrupted revealed that different HDACs target different histones and genes [191, 199]. Additionally, it has been proposed that in fission yeast, different subregions of a coding region are regulated by different HDACs [165]. Additional studies like these will lead to a better understanding of underlying mechanisms of transcriptional regulation by distinct types of histone modification enzymes.

A genome-wide approach to investigate the role of specific sites of histone modification using histone point mutants has also been undertaken. In budding yeast, mutation of Lys16 on histone H4 significantly reduced telomeric silencing, but single mutation of all other lysine residues of histones H3 and H4 had no effect on telomere silencing or global transcription. Only when mutated in combination did the mutations have an effect [158]. In a similar manner, individual histone H3 lysine mutations had little effect on subtelomeric gene silencing or genome-wide expression [200]. These results suggest that some histone residues have a specific function, such as histone H4 Lys16 for transcriptional silencing, but many other residues may act redundantly. Elucidation of the significance of distinct functional modifications from the point of view of independent versus dependent or specific versus redundant functions will lead to a better understanding of the links between histone, nucleosome, and chromatin biochemistry and biology.

These types of genome-wide analyses will ultimately generate a comprehensive picture of the functional role of every histone modification enzyme and modified residue. In future, the application of genome-wide analysis of chromatin structure and function for all the genomic regions and organisms will lead to a better understanding of the unity and diversity of regulatory mechanisms for spatially and temporally distinct expressions of every gene locus.

	CONCLUSION AND PERSPECTIVE

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The study of eukaryotic transcriptional regulation was started with the goal of generalizing the basic principles of Operon theory discovered in bacterial transcription. The result is that we now have a framework for understanding transcriptional regulation of individual genes by sequence-specific DNA-binding proteins.

The fruitful marriage of eukaryotic studies of transcription and histone-mediated reactions clarified two major mechanisms, each functioning at a different level for the regulation of DNA-mediated reactions by specific modification of core histones: a mechanism for regulation of transcription of specific genes in the context of the chromatin template, and a mechanism for transcriptional regulation of a broad array of genes within a certain area of the chromosome. Both mechanisms were found to be, at the same time, specific and broad-based. Histones, and their modifications, possess broad functionality in the sense that they play a global role in a broad array of DNA-mediated reactions. This aspect of histone function implies that fundamental concepts that govern the relationship between transcriptional regulation and histone modification can be applied to many other DNA-mediated reactions. Furthermore, the regulatory role of histone modifications, like acetylation, appears to have been broadly adopted by other proteins, such as p53, extending the functionality of these modifications even more.

Recent advances in the area of chromatin structure and function identified mutations in a variety of chromatin factors that are linked to specific diseases, suggesting that new types of drugs that target chromatin factors may have therapeutic value. The recent record of progress in the area of histone modification suggests the continued need to: (i) identify new HATs/HDACs and other modification enzymes responsible for individual biological pheomena; (ii) characterize modifications and their corresponding interacting partners for histones and other DNA- and/or histone-associated factors; (iii) elucidate a unified model for regulation of chromosome-wide gene expression by histone modification in all regions of the chromosome. A better understanding of the rules that unify histone modifications and DNA-mediated reactions at different chromosomal loci will provide powerful insight into the genetics and epigenetics of nuclear function and disease.

Key Points Post-translational protein acetylation plays pivotal roles in various cellular processes and thus attracts ever-increasing attention. Especially, a considerable number of studies have been conducted on acetylation of histone in transcriptional regulation, leading to proposition of basic models such as histone code hypothesis, which provides general ideas about functional consequences of post-translational modification of histones in nuclear phenomena. In this manuscript, we overview the history of researches on histone acetylation in transcription, and describe the enzymes, reactions and systems involved.

 

	Acknowledgements

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We are grateful to K. Hasegawa, M. Eitoku and Y. Ogawa for helpful assistance and discussions. We thank Dr Wendy Zhow (Great Wall of China), Dr Tim Harrison (American Civil War), Berlin's urban information service (Berlin Wall) and Gifu city museum of history (Battle of Sekigahara) for permissions to use the images presented in Figure 4C. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by Exploratory Research for Advanced Technology (ERATO) of Japan and Technology Agency (JST).

	FOOTNOTES

 
Hiroki Fukuda is a PhD student at the University of Tokyo and is working on the study of chromosome regulation. He is now investigating the mechanism of both the establishment of the chromosomal functional regions and the border regions, and the transition from transcriptionally repressed to activated states.

Norihiko Sano is a student at the University of Tokyo and is working on functional and structural analysis of core histones. Currently he is genetically and biochemically characterizing yeast histone point mutants on DNA-mediated reactions such as transcription, DNA replication and DNA repair.

Shinsuke Muto received his PhD in the lab of Dr Horikoshi working on the biochemical analysis of functional interactions between chromatin factors and sequence-specific DNA-binding transcription factors. He was a member at Horikoshi Gene Selector Project for ERATO.

Masami Horikoshi is an Associate Professor at the University of Tokyo. He was a director at Horikoshi Gene Selector Project (1997–2002) for ERATO. His group focuses on the problems on how gene activities are regulated on chromosomal DNA.

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