Synthetic genome readers target clustered binding sites across diverse chromatin states

Graham S. Erwin, Matthew P. Grieshop, Devesh Bhimsaria, Truman J. Do, José A. Rodríguez-Martínez, Charu Mehta, Kanika Khanna, Scott A. Swanson, Ron Stewart, James A. Thomson, Parameswaran Ramanathan, and Aseem Z. Ansari, PNAS 2016 ; published ahead of print November 8, 2016, doi: 10.1073/pnas.1604847113

Nucleosomal DNA, even in heterochromatin, may thus be partially preorganized to accommodate polyamide binding in the minor groove. The linear polyamide (3) studied here was designed to bind to GAA repeats in the first intron of frataxin to alleviate transcriptional repression, a locus that appears to be situated within heterochromatin marked by H3K9me3. Taken together, the ability of polyamides to access heterochromatin (a major barrier to binding to natural and artificial DNA-binding factors) opens unique opportunities to deploy this class of synthetic genome readers to regulate gene networks that direct cellular fate and function.