Controlling cell fate-determining gene expression is key to stem cell 
differentiation, tissue regeneration, and cancer therapy. To date, custom-built 
transcription factors recognize the information encoded in specific DNA 
sequences. Chromatin proteins undergo covalent modifications and form complexes 
that encode a second layer of information that determines proximal gene 
activity. Here, we employ a novel gene-targeting approach that exploits a 
specific chromatin modification to reactivate silenced loci in human cells. We 
used the human Polycomb chromatin protein and homologues from other species to 
construct modular synthetic transcription factors, called Pc-TFs, that recognize 
the repressive trimethyl-histone H3 lysine 27 (H3K27me3) signal and switch 
silenced genes to an active state. Pc-TF expression in U2OS osteosarcoma cells 
leads to increased transcription of the senescence locus CDKN2A (p16) and other 
loci in a chromodomain- and activation module-dependent manner, a switch to a 
senescence phenotype, and reduced cell proliferation. These results indicate 
that silenced developmental regulators can be reactivated by a synthetic 
transcription factor that interacts with chromatin rather than DNA, resulting in 
an altered cell state. As such, our work extends the flexibility of 
transcription factor engineering and is the first example of chromatin-mediated 
synthetic transcription factor targeting.