Histone acetyltransferases are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on, in general, histone acetylation increases gene expression. In general, histone acetylation is linked to activation and associated with euchromatin. Histone acetyltransferases can also acetylate non-histone proteins, such as nuclear receptors, HATs are traditionally divided into two different classes based on their subcellular localization. Type A HATs are located in the nucleus and are involved in the regulation of expression through acetylation of nucleosomal histones in the context of chromatin. They contain a bromodomain, which helps them recognize and bind to acetylated lysine residues on histone substrates, Gcn5, p300/CBP, and TAFII250 are some examples of type A HATs that cooperate with activators to enhance transcription. Type B HATs are located in the cytoplasm and are responsible for acetylating newly synthesized histones prior to their assembly into nucleosomes and these HATs lack a bromodomain, as their targets are unacetylated. The acetyl groups added by type B HATs to the histones are removed by HDACs once they enter the nucleus and are incorporated into chromatin, Hat1 is one of the few known examples of a type B HAT. Despite this historical classification of HATs, some HAT proteins function in multiple complexes or locations, HATs can be grouped into several different families based on sequence homology as well as shared structural features and functional roles. The Gcn5-related N-acetyltransferase family includes Gcn5, PCAF, Hat1, Elp3, Hpa2, Hpa3, ATF-2 and these HATs are generally characterized by the presence of a bromodomain, and they are found to acetylate lysine residues on histones H2B, H3, and H4. All members of the GNAT family are characterized by up to four conserved motifs found within the catalytic HAT domain and this includes the most highly conserved motif A, which contains an Arg/Gln-X-X-Gly-X-Gly/Ala sequence that is important for acetyl-CoA recognition and binding. The C motif is found in most GNATs, but it is not present in the majority of other known HATs, the yeast Gcn5 HAT is one of the best-characterized members of this family. It has four domains, including an N-terminal domain, a highly conserved catalytic domain, an Ada2 interaction domain. PCAF and GCN5 are mammalian GNATs that share a degree of homology throughout their sequences. These proteins have a 400-residue N-terminal region that is absent in yeast Gcn5, Hat1 was the first HAT protein to be identified. It is responsible for most of the cytoplasmic HAT activity in yeast, Elp3 is an example of a type A HAT found in yeast. It is part of the RNA polymerase II holoenzyme and plays a role in transcriptional elongation, the MYST family of HATs is named after its four founding members MOZ, Ybf2, Sas2, and Tip60. Other important members include Esa1, MOF, MORF, and HBO1 and these HATs are typically characterized by the presence of zinc fingers and chromodomains, and they are found to acetylate lysine residues on histones H2A, H3, and H4
Relative sizes and locations of important domains for representative HATs (HAT = catalytic acetyltransferase domain; Bromo = bromodomain; Chromo = chromodomain; Zn = zinc finger domain). The number of amino acid residues in each HAT is indicated at the right in each example.
Crystal structure of Tetrahymena Gcn5 with bound coenzyme A and histone H3 peptide (PDB 1QSN). The central core (green), flanking N- and C-terminal segments (blue), coenzyme A (orange), and histone peptide (red) are shown.
Catalytic mechanisms of GNAT and MYST family HATs. (A) General mechanism of GNAT HATs. (B) General mechanism of MYST HATs.
Schematic showing the role of HATs in gene transcription.