Systematic identification and functional characterization of transcriptional activators in human cells

We have established a platform to systematically identify and characterize the transcriptional regulatory potential of human proteins in an unbiased manner. By screening over 13,000 proteins in a pooled format, we identified several hundred potent activators, many of which were previously poorly annotated. We also systematically uncovered transactivation domains among the hits, including some that do not adhere to the canonical "acidic blob" model of activation domains. Furthermore, we combined interaction proteomics and chemical inhibitors to delineate the co-factor specificity of both novel and known transcriptional activators, highlighting how even highly related TFs with virtually identical DNA-binding specificities can activate transcription through distinct co-factor complexes.