Synthetic genome readers target clustered binding sites across diverse chromatin states

Significance Targeting specific genomic loci with synthetic molecules remains a major goal in chemistry, biology, and precision medicine. Identifying how synthetic genome readers bind the chromatinized genome in cells would facilitate their development, but doing so remains a formidable challenge. We map the genome-wide binding patterns for two structurally distinct synthetic molecules. To achieve this goal, we couple our cross-linking of small molecules to isolate chromatin approach to next-generation sequencing. In addition to binding high-affinity sites, these molecules, surprisingly, bind clustered low-affinity sites. The data also show that these genome readers target sites in both open and closed chromatin. Our findings highlight the importance of genome-guided design for molecules that will serve as precision-targeted therapeutics.

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