Spreading Chromatin into Chemical Biology

Abstract Epigenetics, broadly defined as the inheritance of non‐Mendelian phenotypic traits, can be more narrowly defined as heritable alterations in states of gene expression (“on” versus “off”) that are not linked to changes in DNA sequence. Moreover, these alterations can persist in the absence of the signals that initiate them, thus suggesting some kind of “memory” to epigenetic forms of regulation. How, for example, during early female mammalian development, is one X chromosome selected to be kept in an active state, while the genetically identical sister X chromosome is “marked” to be inactive, even though they reside in the same nucleus, exposed to the same collection of shared trans‐factors? Once X inactivation occurs, how are these contrasting chromatin states maintained and inherited faithfully through subsequent cell divisions? Chromatin states, whether active (euchromatic) or silent (heterochromatic) are established, maintained, and propagated with remarkable precision during normal development and differentiation. However, mistakes made in establishing and maintaining these chromatin states, often executed by a variety of chromatin‐remodeling activities, can lead to mis‐expression or mis‐silencing of critical downstream gene targets with far‐reaching implications for human biology and disease, notably cancer. Though chromatin biologists have identified many of the “inputs” that are important for controlling chromatin states, the detailed mechanisms by which these processes work remain largely opaque, in part due to the staggering complexity of the chromatin polymer, the physiologically relevant form of our genome. The primary objective of this article is to serve as a “call to arms” for chemists to contribute to the development of the precision tools needed to answer pressing molecular problems in this rapidly moving field.