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.

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Perry J

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