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COSMIC-seq of bioactive hairpin N-methylpyrrole/N-methylimidazole polyamides

ABSTRACT: Regulating desired loci in the genome with sequence-specific DNA-binding molecules is a major goal for the development of precision medicine. Pyrrole–imidazole (Py–Im) polyamides are synthetic molecules that can be rationally de-signed to target specific DNA sequences to both disrupt and recruit transcriptional machinery. While in vitro binding has been extensively studied, in vivo effects are often difficult to predict using current models of binding energetics. Determining the impact of genomic architecture and the local chromatin landscape on polyamide-DNA sequence specificity remains an unresolved question that impedes their utility in vivo. In this report we directly identified polyamide–DNA interaction sites across the entire genome, by covalent crosslinking and capturing these events in the nuclei of human LNCaP cells. This method, termed COSMIC-seq, confirms the ability of hairpin-polyamides, with similar architectures but differing at a single ring position, to retain in vitro specificities and display distinct genome-wide binding profiles. These results underpin the development of Py-Im polyamides as DNA-targeting molecules and the potential for utility as synthetic transcription factors (Syn-TFs) capable of functioning in concert with the cellular regulatory circuitry.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149367 | GEO | 2020/12/02

REPOSITORIES: GEO

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