Deciphering the Histone Code
In the nuclei of all eukaryotic cells, genomic DNA is highly folded, constrained and compacted by histone proteins in a dynamic polymer called chromatin. The distinct levels of chromatin organization are dependent on how DNA wraps around an octamer of core histone proteins. Histones are small basic proteins consisting of a globular domain and a flexible, charged terminus called a histone “tail” that protrudes from the chromatin. Central to our current thinking is that chromatin structure plays an important regulatory role and that multiple signaling pathways converge on histones in order to activate or deactivate genes in response to stimuli. Although the amino acid sequence of histones is quite generic, exquisite variations are provided by covalent modifications (acetylation, phosphorylation, methylation) of specific amino acids in the histone tail domain, which alter contacts with the underlying DNA. The enzymes found to catalyze such chemical modifications of histone tails are highly specific for particular amino acids. The hypothesis is that combinations of distinct modifications occurring at particular sites on the histone tail compose a “histone code” that affects which proteins are capable of interacting with histone-DNA complexes and consequently, how gene activity is regulated.

The histone code hypothesis predicts that the modification marks on the histone tails should provide binding sites for effector proteins. In agreement with this notion, modular protein domains that specifically recognize acetylated (bromodomain) or methylated histone tails (chromodomain) have been identified. It is possible the variations found in such proteins correlate with unique spatial arrangements present in modified histones. Already roughly 50 enzymes are known that selectively modify the histone tail thus providing the means to make a combinatorial ‘histone code’. The heterogeneity of histone modifications found in mammalian cells and the technical limitations to making homogeneous populations of selectively modified histone proteins have prevented their rigorous study. Consequently, very few proteins exhibit a strong correlation with selective interaction with a given histone modification pattern. To determine the relevance of the hypothesis, it would be useful to develop a strategy to identify proteins that bind unique combinatorial modifications of histones.


HISTONE ACETYLATION WITHIN THE NUCLEOSOME
Flash 7 plug-in required.

GENE turned OFF
STEP 1: Bromodomain protein (GREEN) does not recognize target and therefore does not bind histone.
STEP 2: Acetylase enzyme (Pac-Man) comes in and acetylates histone tail. This leaves an acetylated lysine (green ball on histone tail)
STEP 3: Bromodomain protein (GREEN) recognizes acetyl-histone, binds and changes structure to initiate assembly of chromatin-remodelling complex (Blue and yellow subunits)
GENE turned ON