Stable bulged G-quadruplexes in the human genome: identification, experimental validation and functionalization
Issued Date
2023-05-22
Resource Type
eISSN
13624962
Scopus ID
2-s2.0-85159779532
Pubmed ID
37094040
Journal Title
Nucleic acids research
Volume
51
Issue
9
Start Page
4148
End Page
4177
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nucleic acids research Vol.51 No.9 (2023) , 4148-4177
Suggested Citation
Papp C., Mukundan V.T., Jenjaroenpun P., Winnerdy F.R., Ow G.S., Phan A.T., Kuznetsov V.A. Stable bulged G-quadruplexes in the human genome: identification, experimental validation and functionalization. Nucleic acids research Vol.51 No.9 (2023) , 4148-4177. 4177. doi:10.1093/nar/gkad252 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/82880
Title
Stable bulged G-quadruplexes in the human genome: identification, experimental validation and functionalization
Other Contributor(s)
Abstract
DNA sequence composition determines the topology and stability of G-quadruplexes (G4s). Bulged G-quadruplex structures (G4-Bs) are a subset of G4s characterized by 3D conformations with bulges. Current search algorithms fail to capture stable G4-B, making their genome-wide study infeasible. Here, we introduced a large family of computationally defined and experimentally verified potential G4-B forming sequences (pG4-BS). We found 478 263 pG4-BS regions that do not overlap 'canonical' G4-forming sequences in the human genome and are preferentially localized in transcription regulatory regions including R-loops and open chromatin. Over 90% of protein-coding genes contain pG4-BS in their promoter or gene body. We observed generally higher pG4-BS content in R-loops and their flanks, longer genes that are associated with brain tissue, immune and developmental processes. Also, the presence of pG4-BS on both template and non-template strands in promoters is associated with oncogenesis, cardiovascular disease and stemness. Our G4-BS models predicted G4-forming ability in vitro with 91.5% accuracy. Analysis of G4-seq and CUT&Tag data strongly supports the existence of G4-BS conformations genome-wide. We reconstructed a novel G4-B 3D structure located in the E2F8 promoter. This study defines a large family of G4-like sequences, offering new insights into the essential biological functions and potential future therapeutic uses of G4-B.