Histone acetyltransferases (HATs) are a family of proteins that catalyze the formation of an amide bond between the epsilon-amino group of an amino-terminal lysine residue of one of the core histone proteins (H2A, H2B, H3 and H4). Although some non-histone substrates have been reported for some of the HATs (26a, 27a), these proteins are not to be confused with proteins that acetylate the amino-terminal residue of many proteins (i.e. NAT1 and ARD1 in yeast), although there appear to be some sequence similarities between some HATs and these proteins (see ref. 27). Histone acetyltransferases are separated into two types, Type A and Type B, by virtue of their subcellular localization (and hence, function). Type A HATs are located in the nucleus, and many play important roles in the regulation of gene expression by functioning as transcriptional co-activators. Type B HATs are located in the cytoplasm and are intimately involved with chromatin synthesis and assembly of nascent histones into chromosomes. To date, only one Type B HAT has been identified (yeast HAT1 and its homologues in other species).

Acetylation of histones is historically associated with increases in gene expression, while deacetylation is associated with decreases in gene expression (see reviews in references). Recently, it has been determined that the HAT activity of Gcn5 is required for its function as a transcriptional co-activator, further linking histone acetylation and gene activation. There are examples of specific acetylated isoforms of histone H4 associated with transcriptionally silent regions of chromatin, however (i.e., acetylation of H4 at K12 in yeast and Drosophila). Through identification of the proteins that acetylate the core histones, the role that histone acetylation plays in control of gene expression and chromatin synthesis can be determined.

CBP/p300. CBP (CREB Binding Protein) and p300 are distinct but closely related mammalian proteins that have been identified as co-activators of transcription for an ever larger group of cellular and viral transcription factors (see recent review by Goldman et al, 1997). It has been demonstrated that these two proteins, known to interact with the histone acetyltransferase P/CAF (21) also themselves possess HAT activity (9, 16). CBP and p300 are reported to acetylate all four core histones.

Esa1. The ESA1 gene is essential in yeast and encodes a protein with histone acetyltransferase activity (35). Esa1p is a member of the MYST/SAS group of proteins that includes the HAT Tip60 (18). Esa1p has homologues in other species (see alignment), including the Mof protein, which functions to regulate dosage compensation in Drosophila males (26). Recombinant Esa1p does not acetylate nucleosomal histones, but does acetylate histones H4, H3 and H2A (listed in the order of preference, 35). Chicken H2B can be acetylated by Esa1p when presented without other histones. The site usage for each of the histones by Esa1p is as follows: H4-K5>K8=K12=K16. H3 K14. H2A K5>K9=K13=K15. Mutation of the conserved glycine residue at position 315 abolishes HAT activity in vitro (35).

Gcn5. GCN5 was originally identified as a gene required for amino acid biosynthesis in yeast (Hinnebusch, 1983). Subsequent studies revealed it to be a transcriptional co-activator and subunit of the ADA protein complex (see Guarente, 1995 for review). The HAT acticity of Gcn5p was discovered due to its close similarity to a Tetrahymena protein (p55) identified by virtue of its HAT activity (12). Recombinant Gcn5 preferentially acetylates histone H3 at lysine 14 but also acetylates H4 at lysines 8 and 16 (14). Gcn5p is found in a protein complex (SAGA) that is distinct from ADA both functionally and biochemically (). The SAGA complex is larger than ADA and includes members of the TBP-class of Spt proteins (25). SAGA also exhibits the ability to acetylate nucleosomes in vitro and recognizes histone H2B. Certain mutations that abolish the HAT activity of Gcn5p also eliminate its ability to function as a transcriptional co-activator (34, 37). Yeast Gcn5p has a homologue in humans (Candau et al, 1996) and is closely related to the P/CAF protein. For more information on yeast Gcn5p, see YPD link to GCN5.

Hat1. First identified as a gene that complemented a yeast mutant that exhibited reduced levels of H4 HAT activity (6). Recombinant yHat1p acetylates histone H4 at lysines 5 and 12 (6, 17). Human Hat1 acetylates histone H4 at K5 and K12 as well as H2A K5 (23, 36). Based on the substrate specificity of Hat1 and the similarity of a Hat1 associated protein to a subunit of yeast and human Chromatin Assembly Factor, it is likely that Hat1p is involved in acetylation of newly synthesized histones prior to (and possibly linked to) chromatin assembly. A similar enzyme activity has also been purified from maize (Eberharter et al, 1996). More info YPD link HAT1.

p160 family. The p160 family is an expanding group of related proteins that includes p/CIP, ACTR, TIF2/GRIP-1/NcoA-2 and SRC-1/NCoA-1. These proteins interact with nuclear hormone receptors and co-activate transcription (see Glass et al, 1997 for a recent review). SRC-1 was originally identified as a protein that interacts with human progesterone receptor in a yeast two hybrid assay. This protein has been shown to enhance the trancriptional activity of all steroid hormone receptors tested (Onate et al, 1995). Subsequent studies demonstrated that SRC-1 possesses endogenous HAT activity (29) that acetylates free histones and mononucleosomes, primarily labelling H3 (most likely at K9 and K14) and H4. HAT activity of SRC-1 requires a region of the protein corresponding to residues 1107-1217. SRC-1 also interacts with P/CAF in vivo and in vitro. ACTR was identified as a protein that interacted with hRAR-beta in a yeast one hybrid assay (24). ACTR also interacts with RXR/RAR, RXR/TR, and RXR/RXR. The ACTR open reading frame was found to have regions of similarity to SRC-1 and TIF2/GRIP1, two steroid hormone receptor co-activator proteins. The protein can interact with P/CAF and CBP/p300 in co-IP experiments. ACTR exhibits histone acetyltransferase activity, and labels all four core histones in vitro. ACTR effectively uses free histones and mononucleosomes as substrates, labelling histones H3 and H4. The smallest fragment of ACTR that exhibits HAT activity corresponds to aa 1092-1292.

P/CAF. P/CAF (p300/CBP Associated Factor) was first identified as a protein that interactswith CBP and competes for a site on CBP that serves as the binding site for the viral E1A protein. P/CAF exhibits extensive similarity to human and mouse GCN5 over its entire primary amino acid sequence and the C-termius of P/CAF is similar to yeast Gcn5p. P/CAF exhibits histone acetyltransferase activity and can acetylate free H3 and H4 and nucleosomal H3 (9, 21). P/CAF associates with several other transcription factors (Currie et al, 1998; Korzus et al, 1998; Scolnick et al, 1997) and is also reportedly able to acetylate several general RNA pol II transcription factors (Imhof et al, 1997).

TAFII250. TAFII250 is the human version of the largest TBP-Associated Factor. This protein can act as a transcriptional co-activator and contribute to the regulation of promoter selectivity (see Burley, 1996 and Verrijzer and Tjian, 1996 for recent reviews). It has been demonstrated recently that the human TAFII250 (and its homologues in Drosophila and yeast) possesses histone acetyltransferase activity (15). Recombinant Drosophila TAFII230 acetylates histones H3 and H4 in vitro. More info information on the yeast homologue of TAFII250/230 can be found at the Yeast Protein Database (YPD) TAF145.

Tip60. Tip60 (Tat Interacting Protein 60), originally identified as a protein that interacts with HIV-1 Tat protein, was shown to stimulate the ability of Tat to transactivation expression from the HIV-1 promoter (Kamine et al, 1996). Analysis of the primary amino acid sequence of Tip60 revealed a motif exhibiting a high degree of homology to a group of proteins with putative and identified HAT activity. This region of Tip60 is especially homologous to a subset of these proteins termed the MYST family (10, 18, 19, 26). Tip60 represents the first published example of a MYST family protein exhibiting HAT activity (33). However, unpublished findings exist indicating that several other MYST group proteins also possess HAT activity. Additionally, a correction of the original reported primary amino acid sequence of Tip60 changes an arginine to an invariant glycine (QRRGYG) found in the the acetyl-CoA binding pocket of all MYST family and HAT sequences (33; see alignment). The substrate specificity of recombinant Tip60 for free histones is H4>H3>H2A.