Synergistic and tunable human gene activation by combinations of synthetic transcription factors

Abstract

The combination of several TALE-TFs that bind the same gene promoter at different positions induces high and tunable activation, even in heterochromatic genes, and offers the promise of engineering complex synthetic gene expression systems. Mammalian genes are regulated by the cooperative and synergistic actions of many transcription factors. In this study we recapitulate this complex regulation in human cells by targeting endogenous gene promoters, including regions of closed chromatin upstream of silenced genes, with combinations of engineered transcription activator–like effectors (TALEs). These combinations of TALE transcription factors induced substantial gene activation and allowed tuning of gene expression levels that will broadly enable synthetic biology, gene therapy and biotechnology.