Histone modifications, either directly (such as acetyl groups that repel negatively charged DNA to create an open chromatin conformation) or through protein linkers called effectors, regulate the physical properties of chromatin and its corresponding transcriptional state. Effector proteins recognize and bind specific epigenetic marks and subsequently recruit molecular mechanisms to alter chromatin structure. These epigenetic readers determine the functional consequences of histone modifications by translating histone codes into actions.
Effector proteins recognize and bind histone modification marks through effector domains (called modules). These modules recognize specific histone modifications with amino acids that line the binding pocket of the module. At the same time, residues outside the binding pocket (especially at the N+2 and N-2 positions) determine the specificity of the modified histone and amino acid residues (eg H3K4 and H4K20).
Slight changes in residues within or outside the binding pocket allow the identification of similar epigenetic marks. For example, effector proteins can distinguish between mono-, di-, or trimethylation states, with slight changes in the structure of the methyl-binding module. For example, a tudor domain might bind only dimethylated or trimethylated lysines, while a PHD finger module might bind both, or only unmodified lysines.
Multiple histone-binding modules, often present in the same protein or protein complexes, recognize specific combinations of histone modifications. This allows for a more complex histone code in which histone modifications interact with each other rather than being interpreted individually.
Multivalent engagement of histone modifications is important for identifying discrete tagging patterns with complex specificity and enhanced affinity, while also enabling diverse and precise downstream actions. For example, a single epigenetic mark, such as H3K4me3, may activate gene transcription in one context but repress it in another, depending on surrounding marks.
Multiple effector modules in a protein or complex may interact with histone modifications on the same or across histones or nucleosomes. These interactions can be grouped into the following categories: Intranucleosome: It binds to the same nucleosome. Cis-Histone: It binds to the same histone tail. Transhistone: It binds different histone tails. Internucleosome: It binds to different nucleosomes. Adjacent bridging: It binds to adjacent nucleosomes. Discontinuous bridging: It binds to non-adjacent nucleosomes.