G-quadruplexes are nucleic acid sequences that are rich in guanine and are capable of forming a four-stranded structure through Hoogsteen hydrogen bonding. G-rich regions capable of forming G-quadruplex (G4) structures are highly concentrated near promoters and transcription start sites
suggesting a role in gene regulation. They are less often found on the template strand than on the non-template strand where they either inhibit or enhance transcription, respectively. However, their potential role in enhancers and in other distal regulatory elements has not been assessed
yet. Here we show that DNAse hypersensitive (DHS) cis regions with regulatory roles are also enriched in Gs and their G-content correlate with that of their respective promoters. Besides local G4s, the distal cis regions have the capability to form G-quadruplexes together with the promoters, each contributing half of a G4 only. This model is supported more for the non-template strand and we hypothesised that the G4 forming capability of the promoter and the enhancer non-template strand could facilitate their binding together and making the DHS regions accessible for the transcription factory. As G4s are targets of intense research and cancer drug development, we anticipate that our model will induce experimentalists to verify it in the lab and contribute to a better understanding of such a basic phenomenon as gene expression regulation.