G‑quadruplexes as regulatory platforms for human transcription factors: insights from ChIP-seq data

G-quadruplexes (G4s) are non-canonical DNA structures with important regulatory functions. While several transcription factors have been shown to interact with G4s, a comprehensive understanding of this interaction network remains elusive.

Here, we integrated genome-wide predictions of highly stable G-quadruplex sequences with 32,817 ChIP-seq datasets from ChIP-Atlas to systematically map transcription factors and transcription-associated chromatin proteins linked to G4-rich regions in the human genome. Highly stable G4 motifs are non-randomly distributed, showing strong enrichment in gene-dense chromosomes, at promoters, regulatory regions, and repeat elements. Integration with transcription factor binding profiles revealed a broad spectrum of G4-associated proteins, including established interactors such as STAT3, TP53 and CTCF, and the transcription-associated chromatin regulator BRD4, as well as previously unrecognized candidates such as REST, NR3C1, FLI1, and HSF1. Unexpectedly, only a minority of transcription factors were consistently depleted from G4 regions.

Our results indicate that G-quadruplex-prone sequences represent a common genomic feature associated with a number of human transcription factors and chromatin-associated regulatory proteins and support a model in which G4-rich regions act as selective regulatory scaffolds shaping transcription factor occupancy and gene regulation.