Nat. Biotechnol. https://doi.org/10.1038/s41587-019-0296-7 (2019)

Recent work has utilized programmable DNA-binding ligands or catalytically inactive Cas9 to deliver modulators of chromatin modifications to a particular gene locus to alter gene expression. However, these approaches are unable to tune gene expression in a dose-dependent manner using endogenous enzymes. To address this limitation, Chiarella et al. devised a system that utilizes a catalytically inactive Cas9 linked to a FK506-binding protein (FKBP) and a chemical epigenetic modifier (CEM). The CEM consists of FK506 linked to a molecule that binds and recruits chromatin-modifying enzymes, such as the BRD family of bromodomains and CBP, to a locus defined by the guide RNA. The titration of CEMs resulted in a dose-dependent activation of gene expression 48 h after treatment, boosting RNA transcripts from weakly expressed genes with a range of 10–20 fold. RNA-seq analysis confirmed that CEM treatment resulted strong BRD4 recruitment to the promoter region targeted by guide RNA. Overall, the CEM system offers a precise means of stimulating gene expression in a dose-dependent fashion.

Credit: Nature