Nat. Biotechnol. doi:10.1038/nbt.2776

Credit: NAT. BIOTECHNOL.

Certain classes of small molecules can elicit their effects on cellular function through alterations of either chromatin-binding proteins or on chromatin itself. Although techniques such as chromatin immunoprecipitation (ChIP)-seq have been useful to globally map the genomic location of transcription factor binding, there has been a growing need to extend these approaches to small molecules. Anders et al. now report on a new assay called Chem-seq, which uses the same techniques as ChIP but relies on a biotinylated small molecule to allow enrichment using streptavidin beads. This approach can either be used directly on living cells or applied to a cellular extract in cases where the probe cannot penetrate the cell. The authors performed Chem-seq on a biotinylated form of JQ1, an inhibitor of the BET bromodomain family. Comparison of the JQ1 binding sites with ChIP analysis of the individual BET family members BRD2, BRD3 and BRD4 revealed a strong colocalization in DNA binding sites to BRD4, in particular. They tested their in vitro approach on AT5719, an inhibitor of the cyclin-dependent kinase CDK9, and observed a strong correlation in chromatin-binding sites between AT5719 and CDK9. Taken together, Chem-seq could be a useful tool to assist investigators to better elucidate the mechanism of action of small-molecule compounds.