Acetylation of Histones and Transcription-Related Factors (2024)

TABLE 1

Summary of known and putative HATs

GNAT Superfamily

The best-understood set of acetyltransferases is the GNAT (Gcn5-related N-acetyltransferase) superfamily (174), which have been grouped together on the basis of their similarity in several hom*ology regions and acetylation-related motifs (Fig. ​(Fig.1A).1A). This group includes the HAT Gcn5, its close relatives, and at least three more distantly related HATs, Hat1, Elp3, and Hpa2. It also contains a variety of other eukaryotic and prokaryotic acetyltransferases with different substrates, indicating the conservation and wide application of this type of acetylation mechanism throughout evolution. Four sequence motifs whose functions are not yet fully understood—C, D, A, and B, in N-terminal to C-terminal order—define this superfamily. The C motif is found in most of the GNAT family acetyltransferases but not in the majority of known HATs. Motif A is the most highly conserved region, and it is shared with another HAT family, the MYST proteins, described later in this review. Furthermore, it contains an Arg/Gln-X-X-Gly-X-Gly/Ala segment that has been specifically implicated in acetyl-CoA substrate recognition and binding (59, 270).

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FIG. 1

Similarities of GNAT (Gcn5-related N-acetyltransferase) superfamily members. (A) Alignment of GNAT hom*ology motifs A, B, C, and D for HATs and representatives of other types of acetyltransferases. Reversed type indicates consensus sequence residues, as determined by Neuwald and Landsman (174), and solid circles mark residues that are particularly conserved throughout the superfamily. The asterisk indicates the glutamate residue known to be critical for HAT catalysis in yeast Gcn5. At the bottom are several members of another acetyltransferase family, the MYST proteins, that share just the A motif. (B) Alignment of proteins from the Gcn5 subgroup of the GNAT superfamily, showing the location of the HAT domain and bromodomain. Shown at the top is the overall hom*ology region shared by all four proteins, with the similarity between the yeast and human proteins indicated; Tetrahymena Gcn5 has 62% similarity with the three others over this same region. The A2 label designates a region in yeast Gcn5 known to interact with the adaptor protein Ada2 (37). In addition, the N-terminal region of PCAF has been generally defined as its site of interaction with p300/CBP and nuclear receptor coactivator SRC-1 (130, 276); this region and the HAT domain also interact with viral protein E1A (40, 193).

Gcn5.

The first protein identified as an A-type, transcription-related HAT was discovered in the ciliate Tetrahymena thermophila (31). By way of an in-gel assay of nuclear extract chromatographic fractions run on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), a 55-kDa polypeptide (p55) was found to have acetylation activity on free histones (29). Subsequent protein sequencing revealed that it was a hom*olog of Saccharomyces cerevisiae (yeast) Gcn5 (77), previously identified as a transcriptional adaptor (or coactivator) involved in the interaction between certain activators and the transcription complex (17, 154, 213). hom*ologs of Gcn5 have more recently been cloned and sequenced from numerous divergent organisms—such as human (36), mouse (276), Schizosaccharomyces pombe, Drosophila melanogaster (215), Arabidopsis thalania, and Toxoplasma gondii (102)—suggesting that its function is highly conserved throughout the eukaryotes.

To date, yeast Gcn5 (general control nonderepressible-5; also referred to as yGcn5) is the best characterized of the HATs, both structurally and functionally and both in vivo and in vitro. Various studies have mapped and characterized the functional domains of yeast Gcn5, shown in Fig. ​Fig.1B1B (35, 37). These include a C-terminal bromodomain, an Ada2 interaction domain, and the HAT domain, which by use of truncation mutants was found to be required for adaptor-mediated transcriptional activation in vivo (37). The Gcn5 HAT domain was also functionally analyzed by alanine scan mutagenesis. These analyses identified conserved residues critical to HAT activity and demonstrated the direct correlation of Gcn5 HAT function with cell growth, in vivo transcription, and histone acetylation at the Gcn5-dependent HIS3 promoter in vivo (134, 256). A further study with some of these mutants showed that Gcn5's HAT activity has an effect on chromatin remodeling at the PHO5 promoter in vivo (89).

The substrate specificity of Gcn5 has also been investigated. In vitro, recombinant Gcn5 was found to acetylate histone H3 strongly and H4 weakly in a free histone mixture (although histone H4 was acetylated well individually). Protein sequence analysis of these reaction products revealed that the primary sites of acetylation were lysine 14 on histone H3, as shown in Fig. ​Fig.2,2, and lysines 8 and 16 on histone H4 (136). Although recombinant Gcn5 can acetylate free histones efficiently, it is unable to acetylate nucleosomal histones (84, 136, 201), the more physiological substrate, except under special conditions and at high enzyme concentrations (243). Only in the context of multisubunit native complexes such as SAGA and ADA (described later in this review) is Gcn5 able to acetylate nucleosomes effectively, indicating that the influence of other proteins is required to confer this activity.

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FIG. 2

Primary histone acetylation specifities of some of the known HAT proteins in vitro. Shown are the amino acid sequences for the N-terminal tail regions of human histones H2A, H2B, H3, and H4, with lysine residues numbered and arrows indicating the predominant sites used by various HATs in in vitro experiments. TAF_II230 is the Drosophila hom*olog of human TAF_II250 used in site specificity determinations. The above H3 and H4 sequences are nearly identical to those of S. cerevisiae and Drosophila. Specific but relatively nonpreferred or minor sites for certain HATs are not indicated, for example, H4 lysine-8 for Gcn5 and PCAF. It should be noted that lysine specificities may be somewhat expanded or restricted with native HAT complexes and/or on nucleosomal substrates.

In mammals (humans and mice), the Gcn5 subclass of acetyltransferases is represented by two closely related proteins, GCN5 and p300/CREB-binding protein-associated factor (PCAF). These proteins share a remarkable degree of hom*ology (about 70% identity and 80% similarity) throughout their sequences, and a distinguishing feature is an approximately 400-residue amino-terminal region not present in yeast Gcn5 (Fig. ​(Fig.1B)1B) (276); such an extension is seen, however, in Drosophila GCN5 (215). The function of human GCN5 (also known as hGCN5) has also been investigated in vitro and in vivo, and it was found to carry out transcriptional adaptor roles analogous to those of yeast Gcn5 (36). Further studies showed that human GCN5 had HAT activity in vitro (279) and that its HAT domain could successfully substitute for that of yeast Gcn5 in vivo, indicating the evolutionary conservation of this HAT function (257).

The HAT domain of human GCN5 is of course indispensable to its acetylation function, but interestingly, two other domains appear to have an influence on its HAT activity and substrate use. Because of the apparent existence of multiple alternatively spliced versions of human GCN5, the original cDNA clones lacked its N-terminal region. While recombinant short-form human GCN5 could acetylate histone H3 (and to a lesser extent H4) only as free histones (257, 279), the full-length forms of human and mouse GCN5 were recently shown to be competent for the acetylation of nucleosomal histones, implicating the N-terminal region in chromatin substrate recognition (276). The C-terminal bromodomain is another region that apparently has an effect on human GCN5 HAT function, interacting with the DNA-dependent protein kinase holoenzyme, which inhibits GCN5's HAT activity by way of phosphorylation (11). Additional functional aspects of the bromodomain are discussed below.

Structure and mechanism.

Along with mutant studies of yeast GCN5, structure determination of several Gcn5-related proteins has added to our knowledge of the mechanisms of acetylation by these enzymes. The first two GNAT superfamily members to have the crystal structures of their acetyltransferase domains solved were yeast Hat1 (59) and Serratia marcescens aminoglycoside N-acetyltransferase (270), a bacterial enzyme that inactivates certain antibiotics by acetylation. In each case, a truncated, catalytically active fragment of the protein bound to CoA or acetyl-CoA substrate was crystallized. Subsequently, HAT domain structures from the Gcn5 subgroup—Tetrahymena (146, 197) and yeast (241) Gcn5 and human PCAF (48)—and HAT protein Hpa2 (5) were also determined.

The central regions of these six proteins all have very similar topologies, and together they define a fundamental structure for GNAT acetyltransferases. As shown by the example of the Tetrahymena Gcn5 HAT domain in Fig. ​Fig.3,3, the proteins consist of N-terminal and C-terminal domains separated by a deep hydrophobic cleft. A conserved core, formed by a three-stranded β-sheet and an amphipathic α-helix and encompassing GNAT motifs A and D, lies at the bottom of the cleft. The acetyl-CoA substrate binds in part of the cleft and is held between motif A and motif B, which located in the C-terminal domain. One Tetrahymena Gcn5 study in particular (197) provided additional information about HAT function by presenting the structure of a ternary complex containing a histone H3 N-terminal tail peptide as well as the HAT domain and CoA. The histone peptide was shown to occupy the larger part of the cleft, bringing the side chain of acetylatable lysine-14 in proximity to CoA (Fig. ​(Fig.3).3).

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FIG. 3

Stereo diagram of the structure of a HAT domain bound to its substrates. Shown is the GNAT superfamily protein Tetrahymena Gcn5 (blue) with a histone H3 N-terminal tail peptide (red) and CoA (green) bound to its upper and lower clefts, respectively. At the active site, the glutamate-122 residue (aqua), analogous to yeast Gcn5 glutamate-173, catalyzes the transfer of an acetyl group from acetyl-CoA to the lysine-14 sidechain (orange) of H3 peptide. The N termini of both the Gcn5 protein and the H3 peptide are to the left in diagram, and C-termini are to the right.

The catalytic site and mechanism of histone acetylation by Gcn5 have also been defined as a result of the structure determinations and mutational analyses. Acidic residues within the cleft region of yeast Gcn5 were likely candidates to function as a general base for catalysis; of these, only glutamate-173 was conserved among the Gcn5/PCAF hom*ologs and potentially critical for function, since simultaneous alanine substitution of glutamate-173 and phenylalanine-171 led to major defects (256). The position of Tetrahymena Gcn5's glutamate-122 (analogous to yeast glutamate-173) relative to the substrates is shown in Fig. ​Fig.3.3. Further yeast studies used a mutant in which glutamate was replaced with glutamine (which has a similar side chain structure but no acidic group) and found that this mutant was highly defective for HAT activity in vitro (234) and for growth and transcription in vivo (241). It was therefore concluded that the carboxyl moiety of glutamate-173, by deprotonating the lysine substrate, is crucial for the HAT catalytic mechanism and overall function of Gcn5. Altogether, the structural, mutational, and GNAT conservation data were in close agreement for the Gcn5 proteins, also allowing detailed mapping of the substrate-binding determinants (residues critical for acetyl-CoA and histone interaction) (197). With regard to catalysis, however, it should be noted that the critical glutamate residue is only conserved among the direct Gcn5 hom*ologs and PCAF but not the other GNAT HATs or other acetyltransferases. Therefore, in non-Gcn5 acetyltransferases, catalysis may occur through other side chains or by direct nucleophilic attack between the substrates (59).

While the studies described above have focused on GNAT catalytic domains, the bromodomain is another Gcn5 region for which there are structural and functional data suggesting an involvement in HAT function. The bromodomain (whose name is derived from Brahma, the Drosophila protein in which it was first described) (233) is a conserved sequence motif found in PCAF and the Gcn5 hom*ologs as well as a variety of other transcription-related proteins (98). Its precise function is largely unclear, but it has been theorized to be involved in protein-protein interactions (117, 268). In vitro, the bromodomain is not required for recombinant yeast Gcn5 to acetylate free histones (37). However, bromodomain deletion of Gcn5 did cause partial defects in growth and in vivo transcription of certain genes (76, 154) and also resulted in reduced in vitro nucleosome acetylation in the context of a native complex, SAGA (described below) (223), suggesting that the bromodomain does have a HAT-related functional effect. Recent evidence indicates that this effect may involve histone interaction. In vitro binding studies demonstrated that the yeast Gcn5 bromodomain interacts directly with histone H3 and H4 N-terminal tails (181), and a structure determination of the PCAF bromodomain showed that it forms a four-helix bundle with a hydrophobic pocket that binds acetyl-lysine on histone H3 or H4 peptides (53). Together, these results suggest a potential role of HAT bromodomains in contributing to substrate interaction, in addition to possible tethering to chromosomal sites (30) or other protein interactions of a regulatory nature (11, 268).

MYST Family

Another group of evolutionarily related proteins that are known or hypothesized to be HATs is the MYST family, named for its founding members: MOZ, Ybf2/Sas3, Sas2, and Tip60 (23). Additional members have more recently been identified, including yeast Esa1, Drosophila MOF, and human HBO1 and MORF. These proteins are grouped together on the basis of their close sequence similarities (Fig. ​(Fig.4)4) and their possession of a particular acetyltransferase hom*ology region (part of motif A of the GNAT superfamily) (174), as shown in Fig. ​Fig.1A.1A. Although containing regions similar in sequence, the members of the MYST family are involved in a wide range of regulatory functions in various organisms.

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FIG. 4

Alignment of the MYST family of HATs and putative HAT proteins. The MYST hom*ology region is indicated, with the acetyl-CoA-binding site, corresponding to GNAT family motif A, shown as a black box. Z, zinc finger motifs: an atypical C2HC motif in the MYST region (Esa1 diverges from this motif), a typical C2HC in the N-terminal region of HBO1, and two adjacent C4HC3 (or PHD) fingers in MOZ and MORF. C, chromo-like domain found in Esa1, MOF, and Tip60.

p300/CBP

After the discovery of histone acetylation by Gcn5 and PCAF, the critical role of acetyltransferases in transcriptional regulation was also demonstrated by the fact that a pair of previously well-characterized coactivators of multicellular eukaryotes, p300 and its close hom*olog CBP (CREB-binding protein), are themselves HATs (8, 178) and FATs (as described below). The interactions of p300/CBP (p300 and CBP are often referred to as a single entity, since the two proteins are considered structural and functional hom*ologs) with PCAF and GCN5, described above, and with nuclear receptor coactivators, described below, are examples of transcriptional regulatory complexes with multiple acetyltransferase activities.

p300/CBP is a ubiquitously expressed, global transcriptional coactivator that has critical roles in a wide variety of cellular processes, including cell cycle control, differentiation, and apoptosis (81, 211), and mutations in p300 and CBP are associated with certain cancers and other human disease processes (80). On the molecular level, p300/CBP stimulates transcription of specific genes by interacting, either directly or through cofactors, with numerous promoter-binding transcription factors such as CREB, nuclear hormone receptors, and oncoprotein-related activators such as c-Fos, c-Jun, and c-Myb. As described above, p300/CBP also binds the HAT PCAF, an interaction with which adenoviral oncoprotein E1A competes (279). p300/CBP is a large protein of about 300 kDa and more than 2,400 residues, and at least four interaction domains with different sets of factors have been characterized throughout its sequence, as shown in Fig. ​Fig.5.5. Furthermore, its central region contains a bromodomain motif (98, 117), which is also found in the HATs Gcn5, PCAF, and TAF_II250.

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FIG. 5

Domains and interaction regions of the global coactivator HATs p300/CBP. Labeled below the polypeptide diagram are several domains and sequence motifs, including a bromodomain, the HAT domain, and ZZ and TAZ putative zinc fingers (190). Above are indicated some of the proteins demonstrated to interact with p300/CBP at certain regions. PCAF has been shown to interact with two regions of p300/CBP (130).

The HAT activity of p300/CBP was first discovered in an E1A pulldown from HeLa (human) nuclear extract (178) and in direct CBP immunoprecipitations from Cos (primate) cell extracts (8). In vitro studies with recombinant p300 and CBP proteins confirmed that these proteins were indeed HATs, strongly acetylating the amino-terminal tails of all four core histones with little apparent specificity. Unlike other HATs, recombinant p300/CBP was able to acetylate all four histones within nucleosomes as well as in free-histone form. Deletion mutant analysis mapped the HAT domain of p300/CBP to an interior region between the bromodomain and the PCAF/E1A/MyoD/c-Fos interaction region (8, 178). p300/CBP represents a unique class of acetyltransferase, although it may be distantly related to other HATs. Careful sequence analysis identified regions with limited hom*ology to GNAT motifs A, B, and D, in addition to another short motif shared with PCAF and Gcn5 (158). Site-directed mutagenesis demonstrated that all four of these motifs contribute to CBP's HAT function. Furthermore, the connection between p300/CBP's HAT function and transcription in vivo was demonstrated by the fact that a promoter-tethered CBP HAT domain resulted in activation, and HAT-impaired mutant versions showed a direct correlation of acetylation competence with this transcriptional activity (158). p300/CBP's HAT function was also shown to be required for certain types of nuclear receptor-mediated activation in vivo (130).

In addition, the HAT activity of p300/CBP is apparently regulated by other factors. As observed for PCAF, the viral protein E1A and the regulatory protein Twist were shown to bind to p300 and inhibit its HAT activity (40, 96, 187). However, another report indicates that E1A has a HAT-stimulatory effect on CBP (2), suggesting a possible functional difference between p300 and CBP (this study also found that cell cycle-dependent phosphorylation of CBP by Cdk2 increases its HAT activity). Since another study reported no effect of E1A binding on CBP's HAT activity (8), it is possible that these HAT effects are due to experimental discrepancies that need to be resolved.

Overall, p300/CBP is one of the most potent and versatile of the acetyltransferases, consistent with its role as a global coactivator in higher eukaryotes. Like PCAF, p300/CBP is known to acetylate and regulate various transcription-related proteins other than histones. The known FAT substrates of p300/CBP, described later in this review, include HMG I(Y), activators p53, GATA-1, erythroid Krüppel-like factor (EKLF), Drosophila T-cell factor (dTCF), and HIV Tat, nuclear receptor coactivators SRC-1, ACTR, and TIF2, and general factors TFIIE and TFIIF. Another phenomenon relevant to the regulatory activities of p300/CBP is that human chromosomal translocations fusing CBP to either the putative HAT MOZ (23) or the MLL gene (232) can result in leukemogenesis; the mechanisms of these processes, however, and whether they involve HAT or FAT activity remain to be elucidated.

Nuclear Receptor Coactivators

HAT proteins have also been directly implicated in transcriptional activation brought about by hormone signals. The HAT activities of human coactivators ACTR and SRC-1, which interact with nuclear hormone receptors, demonstrate the involvement of acetylation in yet another system of transcriptional regulation and define a unique family of HATs.

SRC-1.

Steroid receptor coactivator-1 (SRC-1), also known as p160 (119) and NCoA-1 in mice (240), is a human nuclear receptor cofactor originally discovered by way of its interaction with the human progesterone receptor (PR) in a yeast two-hybrid screen. In vivo experiments in mammalian cells established the coactivator function of SRC-1, as it was able to stimulate ligand-dependent activation by numerous nuclear receptors, including PR, glucocorticoid receptor (GR), estrogen receptor (ER), thyroid hormone receptor (TR), and retinoid X receptor (RXR) (180). Because of this coactivator function, recombinant SRC-1 was assayed in vitro and found to have HAT activity, acetylating H3 and H4 either as free histones or in mononucleosomes (220). Truncation analysis revealed that the HAT domain is located in the C-terminal region of SRC-1, as diagrammed in Fig. ​Fig.6.6. SRC-1 was known to interact with p300/CBP (119, 214, 280), and interestingly, it also interacted with PCAF in vitro and in vivo (220), indicating that multiple HATs are employed to regulate hormone-signaled transcription. In addition, p300/CBP was recently shown to acetylate SRC-1, an event that is likely relevant to its nuclear receptor coactivator function (43).

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FIG. 6

Alignment of the p160 family of mammalian nuclear receptor coactivators. Indicated are the PAS/basic helix-loop-helix hom*ology (bHLH) domain, nuclear receptor interaction regions, and the general area of interaction for coactivators p300/CBP and PCAF. ACTR and SRC-1 each have a HAT domain near their C terminus (42, 220), although the boundaries of these domains have only been approximately defined, and TIF2's domain is inferred by hom*ology.

See Also

Linking DNA methylation and histone modification: patterns and paradigmsIs Methylation Good or Bad?What is the Difference between DNA Methylation and Histone Acetylation?DNA Methylation: Superior or Subordinate in the Epigenetic Hierarchy?

TBP-Associated Factor TAF_II250

Another direct connection between acetylation and activated transcription was demonstrated with the discovery that one of the TAF_II (TATA-binding protein [TBP]-associated factor) subunits of the general transcription factor TFIID is itself a HAT. Specifically, hom*ologs of this protein—TAF_II250 in humans, TAF_II230 in Drosophila, and Taf_II145/130 in S. cerevisiae—were shown to have HAT activity in vitro (169).

TFIID is one of the general factors required for the assembly of the RNA polymerase II transcription preinitiation complex, along with TFIIA, TFIIB, TFIIE, and TFIIF (32, 97). TFIID is in fact the first factor needed in the stepwise assembly: through its TBP subunit, TFIID binds to specific promoter DNA sequences and allows subsequent formation of the transcription complex. Although TBP without TAF_IIs is able to bind promoters and allow basal transcription in vitro, the TAF_II subunits promote activated transcription. Furthermore, TAF_IIs have been shown to interact with certain activators and initiation-related factors (250).

The potential involvement of acetylation in TAF_II function was realized with the discovery that a 250-kDa band from human nuclear extract (in an in-gel assay) and immunoprecipitated human TFIID had HAT activity (169). Further characterization of the TAF_II HAT activity was performed with recombinant Drosophila TAF_II230, which was found to acetylate H3 (preferentially on lysine-14, like Gcn5) and H4 in a free histone mixture (and H2A as an individual histone). It should be noted that TAF_II250 and its hom*ologs, like the p160 nuclear receptor coactivators, have some of the weaker in vitro HAT activities observed—p300/CBP and PCAF, for example, have more potent activities (130, 177; unpublished results). The in vivo significance of these apparent differences in catalytic strength, however, is not yet known.

Truncation studies with yeast and Drosophila TAF mapped the HAT domain to the conserved central region of the protein. This region has little apparent similarity to other known proteins, so TAF_II250 may define a unique HAT class. However, a potential acetyl-CoA binding site has been identified within this region; it shares a Gly-X-Gly pattern with Gcn5 and other acetyltransferases, and mutation of these glycines led to reduced HAT activity (58). Like Gcn5, PCAF, and p300/CBP, TAF_II250 also has a bromodomain (and Drosophila TAF_II230 has two), but truncation studies demonstrated that it is not required for HAT activity (169); this and the fact that the yeast hom*olog contains no bromodomain argue against a major role for it in TAF_II250's HAT function.

The HAT activity of TAF_II250 and its hom*ologs suggests a model for the initiation of transcription complex formation at chromatin-packaged promoters. Nucleosomes are known to inhibit binding of TBP to the TATA box (164, 273), and this inhibition is apparently mediated by histone tails (82, 115). As part of TFIID, TAF_II250 may well facilitate TBP binding directly by acetylating histones at the TATA box, allowing formation of the preinitiation complex. Also potentially relevant to TAF_II250 function is that TFIID is proposed to contain a histone octamer-like structure (104, 274), which may displace nucleosomal histones in concert with TAF_II250's HAT activity. Although the widespread involvement of TFIID in initiation (including at TATA-less promoters) is expected to bring TAF_II250 to very many genes, recent mutant studies suggest that its HAT activity is required for transcription at only a subset of promoters (e.g., certain cell cycle regulators) (58, 176). The mechanism of this specificity, however, is not yet known.

TFIIIC

Although all of the A-type HATs discussed so far in this review are proposed to be involved with transcription by RNA polymerase II (primarily of mRNA), chromatin structure is expected to affect any kind of transcription, such as the synthesis of rRNA by RNA polymerase I or tRNA precursors by RNA polymerase III. Evidence that histone acetylation is a generally employed mechanism in transcription is the fact that subunits of TFIIIC, a general transcription factor in the RNA polymerase III basal machinery, were also recently identified as HATs (109, 133). The known function of TFIIIC is to initiate transcription complex formation by binding to promoter DNA and recruiting TBP-containing TFIIIB and RNA polymerase III (137). Recent in vitro studies with purified human TFIIIC showed that it harbored HAT activity, acetylating H3, H4, and H2A as free histones and also in nucleosomes. Interestingly, an in-gel assay of TFIIIC revealed that three of its nine subunits have apparent HAT activity. The HAT functions of two of these subunits, TFIIIC110 and TFIIIC90, have been confirmed and further investigated. A bacterially expressed C-terminal fragment of TFIIIC110 had HAT activity in an in-gel assay (133), while recombinant TFIIIC90 was competent for the acetylation of either nucleosomal or free histone H3, with an apparent preference for lysine-14 (like Gcn5 and TAF_II230) (109). Future studies should better clarify the function of these HAT activities in this type of transcription, but a logical hypothesis is that it fulfills a role similar to that of TAF_II250 in the RNA polymerase II transcription complex. In both cases, a HAT enzyme is intimately associated with the first step in DNA binding of the transcription complex and likely acts to destabilize promoters' nucleosomes to facilitate this process. Furthermore, it is reasonable to predict that RNA polymerase I transcription is also associated with HAT activity, although this has not yet been demonstrated.

Yeast HAT Complexes

Most known HATs are able to acetylate free histones in vitro when assayed as a single polypeptide. Many, however, such as Gcn5, are unable to acetylate their probable physiological substrate, nucleosomal histones, under standard conditions in vitro, apparently due to the requirement for other factors to allow this level of substrate specificity. Because of this, a study was performed which sought to identify native yeast complexes capable of acetylating nucleosomal substrates (84). Through fractionation of S. cerevisiae extracts and assays of nucleosomal HAT activity, four distinct complexes were discovered and have been further characterized: SAGA, ADA, NuA4, and NuA3.

SAGA.

After their discovery, the four separable nucleosomal HAT activities were initially analyzed by Western blot and null mutation studies, and it was found that the two nucleosomal histone H3/H2B-specific complexes contained Gcn5 as their HAT catalytic subunit, along with two other transcriptional adaptor proteins, Ada2 and Ada3 (84). Interestingly, one of these complexes also contained several Spt proteins, which were originally identified via another transcription-related genetic screen (suppression of Ty and δ insertions at promoters) (reviewed in reference 267). This complex was therefore named SAGA (Spt-Ada-Gcn5 acetyltransferase) (reviewed in reference 88); the other complex, containing Ada proteins but not Spts, was called ADA (described below).

Of the known HAT-containing complexes, yeast SAGA is the best characterized. It is a large complex, approximately 1.8 MDa, as determined by a sizing column. About 15 of its subunits are now known, although it is expected that at least several more remain to be identified. Notably, SAGA brings together in one complex four different groups of previously described transcription-related proteins: the transcriptional adaptors (Ada proteins), a subset of the Spt proteins, a subset of the Taf_IIs (86), and Tra1 (87, 204), the yeast hom*olog of the human transcriptional regulatory protein TRRAP. Interestingly, human HAT complexes have also been isolated that contain hom*ologs of each of these groups, as shown in Fig. ​Fig.77 and discussed below, suggesting evolutionary conservation of SAGA function (177, 247). In addition, yeast SAGA contains the transcriptional regulator Sin4 (282), which is also a component of the Srb/mediator subcomplex of RNA polymerase II holoenzyme (143, 219).

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FIG. 7

Schematic diagram of known subunits and functions of the yeast SAGA and human PCAF or GCN5 HAT complexes. The yeast SAGA complex (top) contains Gcn5 as its HAT catalytic subunit. SAGA has been shown to interact with acidic activation domains, and this function may be mediated by its adaptor components (Ada2, Ada3, and Gcn5) or possibly through Tra1 or other subunits. Another subset of SAGA proteins (Ada1, Spt7, and Spt20/Ada5) are required for its structural integrity and overall function. The Spt3 and Spt8 subunits have been implicated in interaction with TBP, and the Taf_II group, which also participate in TFIID, may provide TBP-binding function to SAGA as well. The human SAGA-analogous complexes (bottom) contain either GCN5 or PCAF. The PCAF complex has been more thoroughly studied; it has nucleosome acetylation function, and known subunits include TRRAP, hADA2, hADA3, hSPT3, and TAF_IIs/PAFs (PCAF-associated factors)—all hom*ologs of proteins found in SAGA. Activator and TBP interaction functions are hypothesized for these human complexes but have not yet been demonstrated.

The adaptors contained in yeast SAGA are Ada1 (107a), Ada2 (17), Ada3 107b(), Ada5, and Gcn5. The Spt proteins it contains are Spt3 (64a), Spt7 (73), Spt8 (64b), and Spt20, previously described as the TBP-related Spt subgroup because of their apparent functional interactions with TBP. Prior to the discovery of SAGA, there was evidence of an Ada-Spt relationship in that ADA5 and SPT20 represent the same gene, which was discovered in independent genetic screens (153, 196). More recently, analysis of SAGA subunit mutant effects on phenotypes and on SAGA composition and function have shown that the Ada and Spt proteins within SAGA can be placed in three categories reflecting their structural and functional roles in the complex (84, 195, 223). Null mutation of the genes encoding Ada1, Spt7, or Spt20/Ada5 leads to disruption of SAGA and severely impaired growth, indicating the requirement of these subunits for SAGA structural integrity and the significant impact of SAGA loss in vivo. Mutations in either of the other two groups, Ada2/Ada3/Gcn5 and Spt3/Spt8, led to largely intact SAGA and moderately impaired yet distinct phenotypes, consistent with their roles as somewhat peripheral subunits that are involved in specific SAGA subfunctions that have been demonstrated—activator interaction (113, 246) and nucleosome acetylation for Ada2/Ada3/Gcn5 and TBP interaction (15, 86, 195, 223) for Spt3/Spt8.

In vivo and in vitro, the SAGA complex and its components have been shown to be critical to certain types of transcription. In vitro, purified SAGA was able to stimulate transcription in various chromatin-template assays by way of its combined HAT activity and interaction with acidic activators (113, 246, 254). The in vivo significance of SAGA has been demonstrated by examination of mutants of its components, which have verified that the complex has an important role in transcriptional activation at a subset of genes, such as GAL1 (57), TRP3, and HIS3 (15), although its regulatory effect may be distinct at different genes. Interestingly, Gcn5/SAGA and the chromatin-remodeling complex Swi-Snf display apparent genetic interactions (189, 195) and complementarity or partial redundancy with each other in the activation of some genes (19, 90, 229). This suggests that both of these complexes may be recruited to certain promoters and contribute to transcriptional activation by altering chromatin, albeit by different mechanisms (14).

Likely relevant to the in vivo chromatin-modifying function of Gcn5 is the fact that its participation in the SAGA complex has distinct consequences for its histone substrate specificity in vitro. SAGA gives Gcn5 the ability to acetylate nucleosomes, with a primary specificity for histone H3 and, to a lesser extent, H2B (84). This capacity to interact with and recognize nucleosomal histones is apparently conferred by other subunits in the complex and may involve Gcn5's bromodomain, deletion of which significantly reduces nucleosome acetylation by SAGA (223). Participation of Gcn5 in the SAGA complex (and ADA) also causes expanded lysine specificity on histone H3, as determined by a recent study (85). SAGA and ADA significantly acetylated other lysine residues in addition lysine-14 both on H3 N-terminal tail peptides and in nucleosomal H3. The patterns of acetylation by these complexes were overlapping yet distinct, further indicating the influence of other subunits on Gcn5's function.

Future studies should further elucidate the roles of various subunits in the structure and transcriptional function of SAGA. It is notable that SAGA does not contain Taf_II145/130, the Taf_II shown previously to possess HAT activity (169), but it does contain a histone-related Taf_II subgroup (Taf_II20, -25, -60, -68, and -90), which is important for SAGA's acetylation and transcription-stimulation function in vitro (86). These subunits could conceivably provide TBP interaction or histone displacement function, but their specific roles in the context of SAGA remain to be demonstrated. Tra1, the yeast TRRAP hom*olog, also has implications for SAGA structure and function that require further study. Tra1 is an essential protein (204), and its large size (approximately 400 kDa) suggests that it may be important to the overall structure of SAGA. Functionally, its hom*olog TRRAP has coactivator function, interacting with the activators c-Myc and E2F (161), which suggests that it may have an activation domain interaction role like Ada2 (10, 213). Finally, recent evidence indicates that SAGA's composition and function may be dynamic, exhibiting changes depending on conditions in the cell. While SAGA produced from rich medium (transcriptionally repressive for HIS3 and other amino acid-biosynthetic genes) has been well described, derepressing conditions gave rise to another form, termed SAGA_alt (altered SAGA) (15). SAGA_alt lacks the Spt8 subunit and, potentially, its negative regulation of TBP function at HIS3, but this complex and its precise relationship to SAGA await further characterization.

Human HAT Complexes

Recently, several human protein complexes with known HAT subunits have been isolated from nuclear extracts and partially characterized. Subunit identification has shown that some of these complexes are remarkably analogous in composition to known yeast HAT complexes, and in each case an involvement in transcription is also suggested by subunits besides the HAT protein.

Drosophila MSL Complex

Native HAT complexes from S. cerevisiae and human cells have been best characterized, but an interesting complex from another organism—the Drosophila MSL complex—has also recently been partially purified and characterized. As mentioned above, the MSL complex is involved in dosage compensation, i.e., increased transcription from the X chromosome in male fruit flies. It contains at least five proteins: MSL1 (male-specific lethal), MSL2, MSL3, MLE (maleless, an RNA-DNA helicase), and MOF, the HAT catalytic subunit. These proteins colocalize to many sites throughout the X chromosome, and mutation of any of the genes encoding them leads to male-specific lethality (150). Studies with coexpressed proteins have defined some of the interactions among the MSL components, and MSL1 was found to have a central role in assembly of the complex (210). In addition, two noncoding RNAs, transcribed from the genes roX1 and roX2 (RNA on the X), also colocalize with MSL subunits on the X chromosome (72) and copurify with the MSL complex (166, 217).

Immunoprecipitations from Drosophila nuclear extracts have allowed further characterization of the MSL complex in vitro. In HAT assays, the complex acetylated nucleosomes exclusively on lysine-16 of histone H4 in a MOF-dependent manner (217). Since lysine-16-acetylated histone H4 is a hallmark of dosage-compensated chromatin, it is likely that MOF and the MSL complex carry out this acetylation function in vivo as well. It remains to be determined how the MSL complex specifically targets the X chromosome, but one theory is that it gains a foothold through the roX genetic loci, which are part of the X chromosome (122). Other aspects of dosage compensation (e.g., how the specific acetylation causes or is associated with increased levels of transcription) also require further analysis, but it is clear that the MSL complex and its HAT subunit are critical to the overall process.

Versions of the SAGA complex (and possibly NuA4) seem to be conserved throughout the eukaryotes; its existence also in Drosophila is implied by a recent coimmunoprecipitation of dTAF_II24 and dGCN5 (78). The MSL complex, however, may be an example of a specialized HAT complex that is not widely conserved. While dosage compensation in Drosophila apparently involves HAT-mediated activation, it should be noted that other organisms employ different dosage compensation strategies and thus may not possess analogous HAT complexes. In the nematode Caenorhabditis elegans, hermaphrodites experience downregulation of both X chromosomes, and in female mammals, one of the two chromosomes is silenced (165). Instead of an MSL-like complex, these species may therefore use different types of regulatory complexes—which may or may not contain HATs—to control these processes.

TABLE 2

Summary of known FAT substrates^a

Nonhistone Chromatin Proteins

Histones are by far the best-characterized acetylation substrates within chromatin, but most of the high-mobility-group (HMG) chromatin-associated proteins (reviewed in reference 33) are also known to be acetylated. These proteins participate in transcriptional enhanceosome complexes and higher-order chromatin structure, and recent evidence suggests that HMG acetylation is involved in the regulation of these functions.

Transcriptional Activators

Transcriptional activators can be generally defined as proteins that bind to specific sites on promoter DNA and bring about increased transcription of specific genes through interactions with other proteins. As such, they typically contain (i) a DNA-binding domain and (ii) one or more activation domains, which may contact the transcriptional machinery directly or through coactivators and thereby influence transcriptional activity. Acetylation has recently been shown to affect the functions of these domains, either positively or negatively, in a number of activators involved in various cellular and developmental processes.

Nuclear Receptor Coactivators ACTR, SRC-1, and TIF2

As described earlier, nuclear receptor coactivator ACTR is a HAT that interacts with both p300/CBP and PCAF and activates transcription in response to hormone signals. Remarkably, acetylation of ACTR by p300/CBP has recently been demonstrated to regulate ACTR's activation potential—the first example of one acetylase regulating another by FAT activity (43). By truncation and in vitro acetylation studies, the site of acetylation was identified as the central receptor interaction domain. Amino acid substitution experiments and peptide analysis implicated several lysine residues, all adjacent to an LXXLL motif (100), shown previously to be structurally crucial in the interaction of other proteins with hormone-bound receptors (52). Further experiments showed that acetylation by p300 prevented ACTR from binding receptors, apparently by disturbing key interaction surfaces, ultimately leading to loss of ACTR's activation function (43).

The two other members of the p160 family of nuclear receptor coactivators, SRC-1 and TIF2, can also be efficiently acetylated by p300/CBP in vitro (43). Although the consequences of these acetylation events have not yet been studied, the structural and functional parallels of the three coactivator proteins suggest that they may have a similar mode of regulation. Future investigation should resolve this question.

General Transcription Factors TFIIE and TFIIF

Most of the known targets of FAT activities are activators or coactivators of specific sets of genes, but one study has reported that certain general transcription factors can be acetylated as well. When a number of recombinant human general factors (TFIIA, TFIIB, TBP, TFIIE, and TFIIF) were tested in in vitro assays with PCAF, p300/CBP, and TAF_II250, it was found that certain components of TFIIE and TFIIF could be acetylated (116). Specifically, the RAP74 and RAP30 subunits of TFIIF were acetylated by PCAF and p300/CBP, and the β subunit of TFIIE was acetylated by these enzymes as well as by TAF_II250. While these basal factor acetylation events are intriguing, their functions remain to be demonstrated. In vitro transcription studies so far have found no significant effect of TFIIE or TFIIF acetylation on transcription at various promoters (75, 116). Future in vivo studies will likely be required to determine if these factor acetylation events occur physiologically and what, if any, regulatory effects they may have on transcription.

Self-Acetylation and Transcription-Unrelated Substrates

Two other issues that relate to FAT activity but about which relatively little is known are self-acetylation by HATs/FATs and the acetylation of apparently transcription-unrelated substrates, such as α-tubulin and nuclear import factors. Several HATs have been observed to self-acetylate in vitro, including PCAF, p300, Tip60, MORF, Hpa2, and Hpa3. However, it is unknown whether these events have physiological relevance as self-regulation or whether they are merely in vitro artifacts. Further examination of the functional effects of these self-modifications and their occurrence in vivo will be required to resolve this question for each acetylase.

The substrates apparently unrelated to transcription include the microtubule component α-tubulin, known for years to be acetylated in vivo, and two human nuclear import factors, recently demonstrated to be acetylated in vitro by CBP (9). In the case of α-tubulin, lysine-40-acetylated protein has been identified in various organisms (141, 188). This acetylation is known to occur on stabilized microtubules (208), although its actual functional effect is unclear. Since these acetylated microtubules are cytoplasmic, a direct connection to transcription seems unlikely. Very recently, an in vitro screen for potential acetylation substrates of CBP identified Rch1 and importin-α7 (9), two nuclear import factors that function by binding both to nuclear localization signals on various proteins and to importin-β, which mediates import. For Rch1, acetylation was found to have the effect of enhancing the Rch1/importin-β interaction. This result presents the possibility that this modification could promote nuclear import and is another potential example of acetylation regulating cellular processes other than transcription.

Finally, for all of the FAT substrates described above, it should be noted that acetylation is only one type of modification important for the regulation of some these various factors. For example, p53 is also regulated by phosphorylation, and HMG I(Y) is known to receive various types of modifications. Future studies on the functions of FAT substrates must ultimately address the effects of all relevant modifications in order to provide a complete picture of these proteins' regulation.

We thank Y. Nakatani, T. Kouzarides, D. Thanos, S. John, and J. L. Workman for sharing unpublished results; J. R. Rojas, R. C. Trievel, and R. Marmorstein for providing the Tetrahymena Gcn5 structural figure; and B. Stillman, L. Pillus, and C. D. Allis for helpful discussions.

Research support to S.L.B. is provided by the National Institutes for Health/General Medicinal Sciences and National Cancer Institute, the National Science Foundation, and the American Cancer Society, and D.E.S. is supported by an NRSA fellowship from the National Institutes of Health.

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