BACKGROUND: An underlying tenet of the epigenetic code hypothesis is the 
existence of protein domains that can recognize various chromatin structures. To 
date, two major candidates have emerged: (i) the bromodomain, which can 
recognize certain acetylation marks and (ii) the chromodomain, which can 
recognize certain methylation marks.
RESULTS: The Epc-N (Enhancer of Polycomb-N-terminus) domain is formally defined 
herein. This domain is conserved across eukaryotes and is predicted to form a 
right-handed orthogonal four-helix bundle with extended strands at both termini. 
The types of amino acid residues that define the Epc-N domain suggest a role in 
mediating protein-protein interactions, possibly specifically in the context of 
chromatin binding, and the types of proteins in which it is found (known 
components of histone acetyltransferase complexes) strongly suggest a role in 
epigenetic structure formation and/or recognition. There appear to be two major 
Epc-N protein families that can be divided into four unique protein subfamilies. 
Two of these subfamilies (I and II) may be related to one another in that 
subfamily I can be viewed as a plant-specific expansion of subfamily II. The 
other two subfamilies (III and IV) appear to be related to one another by 
duplication events in a primordial fungal-metazoan-mycetozoan ancestor. 
Subfamilies III and IV are further defined by the presence of an evolutionarily 
conserved five-center-zinc-binding motif in the loop connecting the second and 
third helices of the four-helix bundle. This motif appears to consist of a PHD 
followed by a mononuclear Zn knuckle, followed by a PHD-like derivative, and 
will thus be referred to as the PZPM. All non-Epc-N proteins studied thus far 
that contain the PZPM have been implicated in histone methylation and/or gene 
silencing. In addition, an unusual phyletic distribution of Epc-N-containing 
proteins is observed.
CONCLUSION: The data suggest that the Epc-N domain is a protein-protein 
interaction module found in chromatin associated proteins. It is possible that 
the Epc-N domain serves as a direct link between histone acetylation and 
methylation statuses. The unusual phyletic distribution of Epc-N-containing 
proteins may provide a conduit for future insight into how different organisms 
form, perceive and respond to epigenetic information.