Histone lysine acetylation is central to epigenetic control of gene transcription. The bromodomain, found in chromatin-associated proteins and histone acetyltranferases, functions as the sole protein module known to bind acetyl-lysine motifs. Recent structural and functional analyses of bromodomains' recognition of lysine-acetylated peptides derived from major acetylation sites in histones and cellular proteins provide new insights into differences in ligand binding selectivity as well as unifying features of histone recognition by the bromodomains. These new findings highlight the functional importance of bromodomain/acetyl-lysine binding as a pivotal mechanism for regulating protein–protein interactions in histone-directed chromatin remodeling and gene transcription. These new studies also support the notion that functional diversity of a conserved bromodomain structural fold is achieved by evolutionary changes of structurally flexible amino-acid sequences in the ligand binding site such as the ZA and BC loops.

Histone lysine acetylation or methylation helps to regulate chromatin functions during gene transcription. Histone acetylation marks are typically recognized by proteins containing bromodomains, but recently, an alternative mechanism of acetyl-lysine binding was recognized in the tandem plant homeodomain (PHD) finger of human DPF3b, a protein that functions in gene activation. The three-dimensional solution structures of DPF3b bound to a lysine 14-acetylated histone H3 peptide have now been determined, offering mechanistic insight into the way the protein recognizes acetylation marks. The lysine residues of histone proteins can be acetylated or methylated, with important effects on gene expression. Until recently the protein modules that bind acetyl-lysine have been limited to bromodomains. However, the tandem plant homeodomain (PHD) finger of human DPF3b — which is involved in gene activation — has also been reported to bind to acetylated histones. Here, three-dimensional solution structures of DPF3b offer mechanistic insight into how this protein recognizes acetylation marks. Histone lysine acetylation and methylation have an important role during gene transcription in a chromatin context1,2. Knowledge concerning the types of protein modules that can interact with acetyl-lysine has so far been limited to bromodomains1. Recently, a tandem plant homeodomain (PHD) finger3 (PHD1–PHD2, or PHD12) of human DPF3b, which functions in association with the BAF chromatin remodelling complex to initiate gene transcription during heart and muscle development, was reported to bind histones H3 and H4 in an acetylation-sensitive manner4, making it the first alternative to bromodomains for acetyl-lysine binding5. Here we report the structural mechanism of acetylated histone binding by the double PHD fingers of DPF3b. Our three-dimensional solution structures and biochemical analysis of DPF3b highlight the molecular basis of the integrated tandem PHD finger, which acts as one functional unit in the sequence-specific recognition of lysine-14-acetylated histone H3 (H3K14ac). Whereas the interaction with H3 is promoted by acetylation at lysine 14, it is inhibited by methylation at lysine 4, and these opposing influences are important during transcriptional activation of the mouse DPF3b target genes Pitx2 and Jmjd1c. Binding of this tandem protein module to chromatin can thus be regulated by different histone modifications during the initiation of gene transcription.