Histone acetyltransferases (HATs) are the workhorses of the epigenome. These enzymes have a huge role epigenetic regulation of gene expression. They catalyze the transfer of an acetyl group from acetyl-CoA to ε-amino group of a histone lysine residue. These acetylations then serve allow transcriptional access to DNA by either neutralizing the positive histone charge, or serving as a binding site for chromatin remolding complexes.
Histone Acetyltransferase Categories
HATs can be put into two broad categories based on subcellular localization. Type A HATs are found in the nucleus and are responsible for acetylation of histones in chromatin. Type B HATs are found in the cytoplasm and acetylate newly translated histones to facilitate their assembly into nucleosomes (Richman et al., 1988).
HATs can also be put into more defined categories based on structural and functional similarity of their catalytic domains. There are about 30 known HATs in humans grouped into five families. Gcn5-related N-acetyltransferases (GNATs) are named for their similarity to the Gnc5 enzyme. GNATs have 4 conserved motifs forming their HAT domain, and unusually also have bromodomain or chromodomain for binding acetylated or methylated lysine respectively (Neuwald and Landsman, 1997). In general, GNATs are involved in cellular growth (Zhang et al., 1998). MYST HATs are named for their founding members MOZ, Ybf2, Sas2, and Tip60. MYST HATs are characterized by the presence of MYST domain containing an acetyl-CoA binding motif and a zinc finger (Avvakumov and Cote, 2007). Many MYST HATs also have other domains for recognizing other proteins. MYST HATs are involved in control of transcription and cell growth and survival. The other three families are much smaller: the p300/CBP HATs; the general transcription factor HATs, characterized by the presence of the TAF250 domain; and the steroid receptor co-activators (SRC)/nuclear receptor co-activators (NCoA) family (Torchia et al., 1998).
Histone Acetyltransferase Function
One of the most interesting features of HATs is that they are often not specific to individual lysines, yet fulfill specific functions. For example both the SAGA complex and elongator complex acetylate H3K9 and H3K14; however elongator functions in coding regions while SAGA acts at promoters (Wittschieben et al., 1999). The broad catalytic potential of HATs means that its localization to the proper genomic region is vital. The non-catalytic domains of HATs are responsible for directing the protein to the proper location. Chromodomains, bromodomains, PHD finger, tudor, WD40 are some of the major “reader” domains found in HATs that confer specificity (Yun et al., 2011).
HATs act dynamically. HATs and histone deacetylases (HDACs) rapidly turn over acetylation on K4 trimethylated histone H3 tails (Crump et al., 2011). Acetylation is a very transient mark, and it is believed that this is vital for precise temporal transcriptional control. Interestingly, long-lived acetylations have been recently discovered in humans (Zheng et al., 2013). The reason for this longevity is not yet understood.
Histone Acetyltransferase Additional Reading
Berndsen, C.E., and Denu, J.M. (2008). Catalysis and substrate selection by histone/protein lysine acetyltransferases. Curr. Opin. Struct. Biol. 18, 682-689.
This review gives a very detailed look at how HATs actually function mechanistically.
Dekker, F.J., and Haisma, H.J. (2009). Histone acetyl transferases as emerging drug targets. Drug Discov. Today 14, 942-948.
The review examines the possibilities of using HATs as drug targets. The authors give a nice overview of HAT function and classification. They then go into different known pathogenic outcomes of HAT function and how these might be ameliorated using HAT inhibitors.
- Avvakumov, N., and Cote, J. (2007). The MYST family of histone acetyltransferases and their intimate links to cancer. Oncogene 26, 5395-5407.
- Crump, N.T., Hazzalin, C.A., Bowers, E.M., Alani, R.M., Cole, P.A., and Mahadevan, L.C. (2011). Dynamic acetylation of all lysine-4 trimethylated histone H3 is evolutionarily conserved and mediated by p300/CBP. Proc. Natl. Acad. Sci. U. S. A. 108, 7814-7819.
- Neuwald, A.F., and Landsman, D. (1997). GCN5-related histone N-acetyltransferases belong to a diverse superfamily that includes the yeast SPT10 protein. Trends Biochem. Sci. 22, 154-155.
- Richman, R., Chicoine, L.G., Collini, M.P., Cook, R.G., and Allis, C.D. (1988). Micronuclei and the cytoplasm of growing Tetrahymena contain a histone acetylase activity which is highly specific for free histone H4. J. Cell Biol. 106, 1017-1026.
- Torchia, J., Glass, C., and Rosenfeld, M.G. (1998). Co-activators and co-repressors in the integration of transcriptional responses. Curr. Opin. Cell Biol. 10, 373-383.
- Wittschieben, B.O., Otero, G., de Bizemont, T., Fellows, J., Erdjument-Bromage, H., Ohba, R., Li, Y., Allis, C.D., Tempst, P., and Svejstrup, J.Q. (1999). A novel histone acetyltransferase is an integral subunit of elongating RNA polymerase II holoenzyme. Mol. Cell 4, 123-128.
- Yun, M., Wu, J., Workman, J.L., and Li, B. (2011). Readers of histone modifications. Cell Res. 21, 564-578.
- Zhang, W., Bone, J.R., Edmondson, D.G., Turner, B.M., and Roth, S.Y. (1998). Essential and redundant functions of histone acetylation revealed by mutation of target lysines and loss of the Gcn5p acetyltransferase. EMBO J. 17, 3155-3167.
- Zheng, Y., Thomas, P.M., and Kelleher, N.L. (2013). Measurement of acetylation turnover at distinct lysines in human histones identifies long-lived acetylation sites. Nat. Commun. 4, 2203.