Recent advances in synthetic transcription factor design have given scientists new tools for probing genome biology and treating human disease. However, the effects of these designer proteins on the cellular physiology have not been fully characterized. Here we describe the effects of synthetic activators on the DNA methylation status of targeted promoters. Through clonal bisulfite analysis we found that these activators induce a statistically significant decrease in DNA methylation in the targeted region. This study uncovers an important epigenetic effect that synthetic transcriptional activators can induce.