G-quadruplexes are transcription factor binding hubs in human chromatin

• Published in: Genome Biology 2021-04, Vol.22 (1), p.117-117, Article 117
• Main Authors: Spiegel, Jochen, Cuesta, Sergio Martínez, Adhikari, Santosh, Hänsel-Hertsch, Robert, Tannahill, David, Balasubramanian, Shankar
• Format: Article
• Language: English
• Subjects: Binding Sites; Binding, Competitive; Chemical biology; Chromatin; Chromatin - genetics; Chromatin - metabolism; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - genetics; DNA - metabolism; DNA G-quadruplex; DNA methylation; G-Quadruplexes; Gene expression; Gene Expression Regulation; Genome, Human; Genomes; Genomics - methods; Humans; Ligands; Nucleotide sequence; Promoter Regions, Genetic; Protein Binding; Proteins; Recruitment; RNA - chemistry; RNA - genetics; Transcription factor binding; Transcription factors; Transcription Factors - metabolism; Transcription, Genetic
• ISSN: 1474-760X; 1474-7596; 1474-760X
• DOI: 10.1186/s13059-021-02324-z

The binding of transcription factors (TF) to genomic targets is critical in the regulation of gene expression. Short, double-stranded DNA sequence motifs are routinely implicated in TF recruitment, but many questions remain on how binding site specificity is governed. Herein, we reveal a previously unappreciated role for DNA secondary structures as key features for TF recruitment. In a systematic, genome-wide study, we discover that endogenous G-quadruplex secondary structures (G4s) are prevalent TF binding sites in human chromatin. Certain TFs bind G4s with affinities comparable to double-stranded DNA targets. We demonstrate that, in a chromatin context, this binding interaction is competed out with a small molecule. Notably, endogenous G4s are prominent binding sites for a large number of TFs, particularly at promoters of highly expressed genes. Our results reveal a novel non-canonical mechanism for TF binding whereby G4s operate as common binding hubs for many different TFs to promote increased transcription.