Synthetic Chromatin Approaches To Probe the Writing and Erasing of Histone Modifications

Posttranslational modifications (PTMs) of chromatin are involved in gene regulation, thereby contributing to cell differentiation, lineage determination, and organism development. Discrete chromatin states are established by the action of a large set of enzymes that catalyze the deposition, propagation, and removal of histone PTMs, thereby modulating gene expression. Given their central role in determining and maintaining cellular phenotype, as well as in controlling chromatin processes such as DNA repair, the dysregulation of these enzymes can have serious consequences, and can result in cancer and neurodegenerative diseases. Thus, such chromatin regulator proteins are promising drug targets. However, they are often present in large, modular protein complexes that specifically recognize target chromatin regions and exhibit intricate regulation through preexisting histone marks. This renders the study of their enzymatic mechanisms complex. Recent developments in the chemical production of defined chromatin substrates show great promise for improving our understanding of the activity of chromatin regulator complexes at the molecular level. Herein I discuss examples highlighting the application of synthetic chromatin to study the enzymatic mechanisms and regulatory pathways of these crucial protein complexes in detail, with potential implications for assay development in pharmacological research.