Histone modifications regulate the physical properties of chromatin, and its corresponding transcriptional state, either directly (eg acetyl groups that repel negatively charged DNA to create open chromatin conformation) or via protein adaptors termed effectors. Effector proteins recognize and bind to specific epigenetic marks, and subsequently, recruit molecular machinery to alter chromatin structure. These epigenetic readers determine the functional outcome of histone modifications by translating the histone code into action.

Effector proteins recognize and bind to histone modification marks through effector domains, known as modules.

Recognition of histone marks by modules or histone-binding proteins

These modules recognize specific histone modifications with amino acids that line the module’s binding pocket. Meanwhile, residues outside of this binding pocket (particularly in the N⁺² and N^-2 positions) dictate specificity for the histone and amino acid residue being modified (eg H3K4 vs H4K20).

Slight variations in residues within or outside of the binding pocket allow for recognition of similar epigenetic marks. For example, effector proteins can distinguish between mono-, di-, or tri-methylation states with slight variations to the methyl-binding module’s structure. For example, tudor domains may exclusively bind di- or tri-methylated lysines, while PHD finger modules may bind to both, or only to unmodified lysines.

Multiple histone-binding modules are often found in the same protein, and/or protein complex, that enable recognition of specific combinations of histone modifications. This allows for a more complex histone code, where histone modifications interact with each other rather than being interpreted in isolation.

Multivalent engagement of histone modifications is important for recognizing discrete marking patterns with composite specificity and enhanced affinity, while also enabling diverse and precise downstream actions. For example, a single epigenetic mark (like H3K4me3) may activate gene transcription in one context, but repress it in another, depending on the surrounding marks. Table 4 shows examples of some of the functional associations of different combinations of histone modifications.

Multiple effector modules in a protein or complex may interact with histone modifications on the same, or across, histones and/or nucleosomes. These interactions may be categorized as follows:

Intranucleosomal: binding to the same nucleosome

• Cis-histone: binding to the same histone tail
• Trans-histone: binding to different histone tails

Internucleosomal: binding to different nucleosomes

• Adjacent bridging: binding to adjacent nucleosomes
• Discontinuous bridging: binding to nonadjacent nucleosomes

References

1. Ruthenburg, A.J., , Li, H., , et al. Multivalent engagement of chromatin modifications by linked binding modules. Nature Rev. Mol. Cell Biol. 8 , (2007)