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BRD1 (BRPF2) has multiple domains, including two PHD fingers, PHD1 and PHD2. PHD fingers have been shown to bind to methylated and unmethylated histones. That the first PHD finger of BRD1 specifically recognizes the N-terminal tail of unmodified histone H3. And bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the N-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducing the signal carried by acetylated lysine residues and translating it into various normal or abnormal phenotypes. The regulation of chromosome dynamics determines the outcome of numerous nuclear processes such as transcription, DNA repair, recombination, and replication. Furthermore, extensive loss of histone H4 Lys16 acetylation and Lys20 tri-methylation is a feature of human cancer, and the analysis of global changes in histone modification patterns is envisaged as a prognostic marker in prostate cancer treatment. Lysine acetylation is a reversible post translational modification of proteins that initially was studied in histone regulation, chromatin remodeling and gene expression and recently shown to modulate diverse cellular processes, including cell cycle regulation, RNA splicing, nuclear transport and actin nucleation.
MOZ (monocytic leukemic zinc-finger protein) and MORF (MOZ-related factor) are histone acetyltransferases important for HOX gene expression as well as embryo and postnatal development. Along with the catalytic subunits KAT6A and KAT6B, the MOZ/MORF complexes contain adaptor proteins BRPF1/2/3 (bromodomain PHD finger proteins 1, 2, or 3), ING5 (inhibitor of growth 5), and hEAF6 (homolog of Esa1-associated factor 6) (Fig. 1A). Of the four subunits, the three KAT6A/B, BRPF1/2/3, and ING5 contain PTM readers, including a bromodomain (BD), a PWWP domain, and a number of PHD fingers, organization and functions of which differ substantially (Fig. 1B). The tandem PHD fingers in the catalytic KAT6A/B subunit are coupled to form a distinct module-the double PHD finger (DPF). The BRPF1/2/3 subunit has an assembly of two PHD fingers closely linked by a zinc knuckle, named a PZP module, and a typical single PHD finger is seen in ING5.
It has been proved that histone modifiers, such as histone acetyltransferase complexes, function in a stepwise manner. First, they receive and interpret signals (e.g. histone modification patterns), which are site-specific and are recruited to the target sites. They are then further stabilized on the chromatin template to allow the core protein (e.g. MOZ / MORF) to function effectively with its substrate. For primary recruitment, multivalent interactions may bring complex substrate specificity, which is greater than the intrinsic specificity of any of the discrete binding interactions. As for MOZ/MORF complexes, BRD1 plays potential roles in regulating their preference for histone H3. For the secondary stabilization, multiple modest interactions may drastically improve the substrate affinity through an increase in the probability of rebinding to one of the effector modules in the same complex. In the case of the MOZ/MORF complex, the PHD1 fingers of BRD1 proteins are required to strengthen the binding of MOZ/MORF to their substrates. In vitro histone acetyltransferase assay showed the HAT activity of MORF toward H3 peptide increased when BRPF1 was added. Dimethylation of H3K4, but not H3K9, antagonized this increase in HAT activity, consistent with the histone binding affinity of PHD1. The ChIP assay also showed that disrupting the interaction between BRPF2-PHD1 and histones did not eliminate its targeting of the HOXA9 locus. One explanation is that the interaction between BRD1 and unH3 is not involved in the recruitment of the MOZ/MORF complex to the target sites; rather, its role is to strengthen the combination with chromatin.
Fig 1. The MOZ/MORF composition. (Klein et al. Epigenetics. 2014;9(2):186-193.).