Figure 3: Regulatory outcome of different categories of engineered reprogramming TFs. ( a ) TALEs coupled with TADs can be engineered to switch on otherwise silenced reprogramming TFs. By targeting the distal enhancer of Oct4 its expression is activated. The resulting gene expression program is expected to resemble the wild-type scenario. ( b ) When potent TADs are fused to reprogramming TFs the chimeric protein is expected to target genomic regions reminiscent of the unmodified wild-type protein ( a ). However, the presence of a potent TAD elevates expression levels as compared to the wild-type and may also trigger the activation of genes that would otherwise be silent. ( c ) Rationally placed point mutations within the DNA binding domain can modify DNA recognition principles and alter the genomic binding profile. The cartoon represents a synthetic Oct4 with modified binding preferences that leads to the activation of genes that the wild-type protein would not switch on. TFs: transcription factors; TALEs: transcription activator-like effectors; TAD: transactivation domain; Oct4: octamer binding protein 4.