Domain cross-talk in regulation of histone modifications: Molecular mechanisms and targeting opportunities

Functional cross-talk between the catalytic and reader domains in chromatin-modifying enzymes and protein complexes enable coordinated regulation of chromatin modification status, and consequently impacts chromatin-associated processes. ZZ domains are a recently identified class of chromatin readers that recognize the N-terminal region of histone H3 to direct and regulate acetylation activity of several histone acetylation complexes. Cross-talk between chromatin readers sensitive to methylation, and catalytic domains of methyltransferases and demethylases impacts substrate specificity, catalytic activity, and propagation of chromatin marks. Recently described allosteric ligands that target domain communication highlight the potential of domain cross-talk in the development of the next-generation of chromatin-directed therapeutics. •ZZ domain readers direct and regulate chromatin acetylation.•Domain cross-talk allows for exclusion of the opposing chromatin signals.•Positive feedback regulation in chromatin modifiers enables propagation.•EED-targeted ligands allosterically modulate the catalytic activity of PRC2.