G-quadruplex structures are transcriptional regulatory hubs of super-enhancers

G-quadruplexes (G4s) are noncanonical nucleic acid structures with established roles in cis-regulatory elements, particularly promoters, where they influence transcription and genome regulation. Yet, whether G4s also contribute to the activity of enhancers - especially super-enhancers (SEs), which control key cell identity genes and oncogenic drivers - remains largely unexplored. To address this gap, we performed a genome-wide analysis across multiple cell lines to examine the relationship between G4 structures and SEs. We found that G4s are markedly enriched in SEs compared with typical enhancers and are closely linked to features of regulatory activity, including accessible chromatin, active histone modifications, and elevated transcription. Importantly, G4 structures, rather than predicted G4 motifs, underlie this enrichment. We further show that G4-enriched SEs serve as hubs for transcription factor binding, including core regulatory circuits that sustain cancer cell states, and that their target genes are strongly connected to oncogenic pathways. Notably, the highest G4 signals occur in SEs conserved across cancer cell lines, pointing to a fundamental role in maintaining malignant transcriptional programs. Together, our study uncovered G4 structures as integral components of SE biology and highlights them as potential targets for therapeutic disruption of oncogenic gene regulation.