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 113 (47) E7418-E7427; published ahead of print November 8, 2016, doi: 10.1073/pnas.1604847113

The linear polyamide (3) studied here was designed to bind to GAA repeats in the first intron of frataxin, 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. Linear 3, designed to target 5′-AAGAAGAAG-3′, is designed to target a GAA repeat expansion found in patients with Friedreich’s ataxia to alleviate transcriptional repression.
The COSMIC-seq approach that we describe here is a robust and broadly applicable method that can be readily extended to map the genome-wide binding properties of other classes of DNAbinding molecules, including several genome-directed therapeutics. COSMIC-seq will be instrumental in the genome-guided design of molecules that serve as precision-targeted therapeutics.