Decoding G-quadruplex stability: the role of loop architecture and sequence context in the human genome

Area of Science:

• Genomics
• Structural Biology
• Bioinformatics

Background:

• Guanine-rich sequences form G-quadruplex (G4) structures in the human genome, influencing regulatory processes.
• Loop architecture (length, composition) is known to affect G4 stability, but studies often use synthetic sequences.
• Genomic context's role in G4 stability remains less understood compared to in vitro studies.

Purpose of the Study:

• To investigate the relationship between G-quadruplex (G4) chain composition and stability within the human genome.
• To clarify how loop architecture and genomic context influence G4 structural stability using high-throughput sequencing data.

Main Methods:

• Utilized G4-seq and G4-miner to identify G-quadruplexes (G4s) in the human genome via sequencing data.
• Analyzed the correlation between total and individual loop lengths and G4 stability.
• Employed molecular dynamics simulations with native flanking sequences to assess genomic context effects.

Main Results:

• A negative correlation was observed between total loop length and G4 stability.
• Individual loop length distributions showed minimal influence on G4 stability.
• Short-looped G4s in the genome, often as microsatellites, exhibit stability profiles differing from synthetic G4s.
• Genomic context, including flanking sequences, is crucial for determining G4 stability.

Conclusions:

• G4 stability in the human genome is primarily influenced by total loop length and genomic context, rather than individual loop lengths.
• Genomic context significantly alters G4 stability compared to in vitro findings.
• Further research is needed to explore non-canonical G4s and their genomic implications.