The Evolution of Hats: From Past to Present

Histone acetyltransferases (HATs) 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 and off. In general, histone acetylation increases gene expression. In general, histone acetylation is linked to transcriptional activation and associated with euchromatin. Euchromatin, which is less densely compact, allows transcription factors to bind more easily to regulatory sites on DNA, causing transcriptional activation. When it was first discovered, it was thought that acetylation of lysine neutralizes the positive charge normally present, thus reducing affinity between histone and (negatively charged) DNA, which renders DNA more accessible to transcription factors. Research has emerged, since, to show that lysine acetylation and other posttranslational modifications of histones generate binding sites for specific protein–protein interaction domains, such as the acetyllysine-binding bromodomain. Histone acetyltransferases can also acetylate non-histone proteins, such as nuclear receptors and other transcription factors to facilitate gene expression. == hat families == 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 gene 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. Key Concepts and Fundamentals 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. 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 and would thus not easily fit into a particular class. Understanding the Core Elements === Gcn5-related N-acetyltransferases (GNATs) === 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 (GNAT) family includes Gcn5, PCAF, Hat1, Elp3, Hpa2, Hpa3, ATF-2, and Nut1. 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 (A-D) found within the catalytic HAT domain. 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 (general control nonderepressible-5) HAT is one of the best-characterized members of this family. It has four functional domains, including an N-terminal domain, a highly conserved catalytic (HAT) domain, an Ada2 interaction domain, and a C-terminal bromodomain. PCAF (p300/CBP-associated factor) and GCN5 are mammalian GNATs that share a high degree of homology throughout their sequences. Important Considerations These proteins have a 400-residue N-terminal region that is absent in yeast Gcn5, but their HAT functions are evolutionarily conserved with respect to the latter. Hat1 was the first HAT protein to be identified. It is responsible for most of the cytoplasmic HAT activity in yeast, and it binds strongly to histone H4 by virtue of its association with an additional subunit, Hat2. 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. === MYST HATs === The MYST family of HATs is named after its four founding members MOZ, Ybf2 (Sas3), Sas2, and Tip60….