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Publications

Journal Article Ppublish

PubMed: 39658038 DOI: 10.1093/nar/gkae1180

Long G4-rich enhancers target promoters via a G4 DNA-based mechanism.

Nucleic Acids Res 53(2)

Authors: Jeffrey D DeMeis, Justin T Roberts, Haley A Delcher, Noel L Godang, Alexander B Coley, Cana L Brown, Michael H Shaw, Sayema Naaz, Ayush Dahal, Shahem Y Alqudah, Kevin N Nguyen, Anita D Nguyen, Sunita S Paudel, John E Shell, Suhas S Patil, Hong Dang, Wanda K O'Neal, Michael R Knowles, Dominika Houserova, Mark N Gillespie, Glen M Borchert

Affiliations

  • Department of Pharmacology, University of South Alabama, 5795 USA Drive North, Mobile, AL 36688, USA.
  • Department of Engineering, University of South Alabama, 150 Student Services Drive, Mobile, AL 36688, USA.
  • Department of Biomedical Sciences, University of South Alabama, 5721 USA Drive North, Mobile, AL 36688, USA.
  • Marsico Lung Institute, University of North Carolina at Chapel Hill School of Medicine Cystic Fibrosis/Pulmonary Research & Treatment Center, 125 Mason Farm Road, Chapel Hill, NC 27599-7248, USA.
  • Center for Cellular and Molecular Therapeutics at Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA.

Abstract

Several studies have now described instances where G-rich sequences in promoters and enhancers regulate gene expression through forming G-quadruplex (G4) structures. Relatedly, our group recently identified 301 long genomic stretches significantly enriched for minimal G4 motifs (LG4s) in humans and found the majority of these overlap annotated enhancers, and furthermore, that the promoters regulated by these LG4 enhancers are similarly enriched with G4-capable sequences. While the generally accepted model for enhancer:promoter specificity maintains that interactions are dictated by enhancer- and promoter-bound transcriptional activator proteins, the current study tested an alternative hypothesis: that LG4 enhancers interact with cognate promoters via a direct G4:G4 DNA-based mechanism. This work establishes the nuclear proximity of LG4 enhancer:promoter pairs, biochemically demonstrates the ability of individual LG4 single-stranded DNAs (ssDNAs) to directly interact target promoter ssDNAs, and confirms that these interactions, as well as the ability of LG4 enhancers to activate target promoters in culture, are mediated by G4 DNA.

MeSH

Genes, Promoter Regions, Genetic, Nucleic Acids, Enhancer Elements, Genetic, Dna

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