Acetylation of the epsilon-amino group of lysine residues, or N(epsilon)-lysine acetylation, is an important post-translational modification known to occur in histones, transcription factors and other proteins. Since 1995, dozens of proteins have been discovered to possess intrinsic lysine acetyltransferase activity. Although most of these enzymes were first identified as histone acetyltransferases and then tested for activities towards other proteins, acetyltransferases only modifying non-histone proteins have also been identified. Lysine acetyltransferases form different groups, three of which are Gcn5/PCAF, p300/CBP and MYST proteins. While members of the former two groups mainly function as transcriptional co-activators, emerging evidence suggests that MYST proteins, such as Esa1, Sas2, MOF, TIP60, MOZ and MORF, have diverse roles in various nuclear processes. Aberrant lysine acetylation has been implicated in oncogenesis. The genes for p300, CBP, MOZ and MORF are rearranged in recurrent leukemia-associated chromosomal abnormalities. Consistent with their roles in leukemogenesis, these acetyltransferases interact with Runx1 (or AML1), one of the most frequent targets of chromosomal translocations in leukemia. Therefore, the diverse superfamily of lysine acetyltransferases executes an acetylation program that is important for different cellular processes and perturbation of such a program may cause the development of cancer and other diseases.

Three fundamental issues in postgenomic biology are (i) how the amino acid sequence of a given human protein predicates its structure, function, and regulation; (ii) how a protein is compared to its paralogs, as well as to its orthologs and other homologous proteins in model organisms; and (iii) how related studies contribute to the understanding of human pathology and the development of efficacious diagnostic and therapeutic means. These fascinating issues have inspired us to conduct a comprehensive analysis of information available on class II histone deacetylases (HDACs). In what follows, we will start with a brief description of different classes of HDACs and then compare class II HDACs from yeast and higher organisms in terms of domain organization, function, and regulation. We will also discuss evidence that links class II human HDACs to cardiomyopathy, osteodystrophy, neurodegenerative disorders, and cancer and will propose that, in addition to inhibitors, activators of these HDACs are of potential therapeutic value.

Histone acetyltransferases (HATs) assemble into multisubunit complexes in order to target distinct lysine residues on nucleosomal histones. Here, we characterize native HAT complexes assembled by the BRPF family of scaffold proteins. Their plant homeodomain (PHD)-Zn knuckle-PHD domain is essential for binding chromatin and is restricted to unmethylated H3K4, a specificity that is reversed by the associated ING subunit. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as catalytic acetyltransferase subunit. Interestingly, while the previously reported HBO1 complexes containing JADE scaffold proteins target histone H4, the HBO1-BRPF1 complex acetylates only H3 in chromatin. We mapped a small region to the N terminus of scaffold proteins responsible for histone tail selection on chromatin. Thus, alternate choice of subunits associated with HBO1 can switch its specificity between H4 and H3 tails. These results uncover a crucial new role for associated proteins within HAT complexes, previously thought to be intrinsic to the catalytic subunit.