Quantitative dialing of gene expression via precision targeting of KRAB repressor

Abstract Human genes are regulated quantitatively, yet the ability to specify the expression level of a native gene accurately and specifically using a defined reagent has remained elusive. Here we show that precise targeting of KRAB repressive domain within regulatory DNA unlocks an endogenous quantitative ‘dial’ that can be engaged at nucleotide resolution to program expression levels across a wide physiologic range, with single-gene specificity and high reproducibly in primary cells.