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Single-Molecule Fluorescence Visualization of DNA Polymerase Dynamics at G-Quadruplexes
Published on: April 4, 2025
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Stable bulged G-quadruplexes in the human genome: identification, experimental validation and functionalization
Csaba Papp1, Vineeth T Mukundan2, Piroon Jenjaroenpun3,4
1Department of Urology, Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Nucleic Acids Research
|April 24, 2023
Summary
Researchers identified novel bulged G-quadruplex forming sequences (G4-Bs) in the human genome. These sequences are prevalent in regulatory regions and linked to disease, offering new therapeutic targets.
Area of Science:
- Genomics
- Structural Biology
- Bioinformatics
Background:
- DNA sequence dictates G-quadruplex (G4) topology and stability.
- Bulged G-quadruplex structures (G4-Bs) possess unique 3D conformations.
- Existing algorithms cannot identify stable G4-Bs, hindering genome-wide analysis.
Purpose of the Study:
- To introduce a novel family of potential G4-B forming sequences (pG4-BS).
- To investigate the genomic distribution and biological relevance of pG4-BS.
- To validate computational models for G4-B formation prediction.
Main Methods:
- Computational identification of pG4-BS.
- Experimental verification of predicted sequences.
- Genome-wide analysis of pG4-BS localization and association with genomic features (R-loops, open chromatin).
- Correlation analysis with gene length, tissue association, and disease states.
- In vitro G4 formation assays.
- Analysis of G4-seq and CUT&Tag data.
- 3D structure reconstruction of a novel G4-B.
Main Results:
- Identified 478,263 pG4-BS regions, distinct from canonical G4s.
- pG4-BS are enriched in transcription regulatory regions, including R-loops and open chromatin.
- Over 90% of protein-coding genes harbor pG4-BS in promoters or gene bodies.
- Higher pG4-BS content correlates with R-loops, longer genes, brain tissue, immune/developmental processes.
- pG4-BS presence in promoters is linked to oncogenesis, cardiovascular disease, and stemness.
- Computational models achieved 91.5% accuracy in predicting G4 formation in vitro.
- Genomic data support the widespread existence of G4-BS conformations.
- A novel G4-B structure in the E2F8 promoter was reconstructed.
Conclusions:
- A comprehensive catalog of G4-like sequences (pG4-BS) has been defined.
- pG4-BS play significant roles in gene regulation and are implicated in various diseases.
- This discovery provides new insights into G4-B biology and potential therapeutic applications.
