Ultra-Specific G-Quadruplex–Colistin Interaction for Efficient Transcriptome-Wide G4 Mapping

G-quadruplexes (G4s) are challenging targets for chemical biology interventions, notably because of their dynamic topological polymorphism. We found that the antibiotic small- molecule colistin (COL) interacts specifically with a single subtype of G4 structures, the so-called parallel G4s. This interaction triggers the aggregation of the G4/COL complexes in a structure-specific manner, which can thus be separated from the bulk solution by centrifugation. This unprecedented mode of affinity-precipitation was exploited here to design the COL-induced RNA G4 precipitation and sequencing (CoRP-seq) protocol, which allows for the assessment of the prevalence of RNA G4s in the transcriptome of human cells in a straightforward manner. CoRP-seq shines by its ultraspecificity, simplicity, and practical convenience, which thus advances G4 mapping further and addresses unmet needs in the field of G4omics.