Borchert lab research challenges longstanding view of gene regulation

Glen Borchert, Ph.D., a professor of pharmacology, is leading the pioneering research.

By Michelle Ryan-Day

A groundbreaking study from researchers at the Frederick P. Whiddon College of Medicine at the University of South Alabama could redefine how scientists understand the role of DNA in regulating genes. Published in the prestigious peer-reviewed journal Nucleic Acids Research, the study introduces a revolutionary concept—that DNA itself plays a direct and active role in the regulation of gene expression, challenging traditional views that proteins are the sole mediators of this process.  

Led by Glen Borchert, Ph.D., a professor of pharmacology in the Whiddon College of Medicine and a professor of biology in the College of Arts and Sciences, this pioneering research focuses on a specific DNA structure known as Long G4 stretches (LG4s). The Borchert lab first described LG4s in the human genome in 2020, identifying approximately 300 such regions. These stretches, which do not follow the typical double-helix structure, instead form complex, knot-like structures called G4-kissing structures.  

That research was published in the lab’s first Nucleic Acids Research paper in 2020.   

“We've been investigating cellular functions of these ever since we first described them,” he said.  

In the new study, Borchert and his team show that these unique DNA structures can directly interact with genomic promoters—the parts of the genome responsible for regulating gene activity.   

For the first time, researchers demonstrated that genes and their enhancers can connect through direct DNA binding, without the involvement of proteins. This discovery directly challenges the long-standing theory that proteins are necessary for genomic looping, a process by which genes and their enhancers come into close proximity to regulate gene expression.  

“Our paper is the first to show genomic enhancers associate with the genes they regulate by the DNAs directly binding (not bound proteins),” he said, “and more fundamentally, our paper directly challenges the notion that DNA is strictly informational. Our work shows DNA is an active participant in gene expression.”  

This discovery opens the door to new possibilities for understanding gene regulation, which could have far-reaching implications for human health, including insights into genetic diseases and potential therapeutic approaches.   

The findings suggest that DNA-based regulatory mechanisms, like those described in the study, play an important role in the regulation of human gene expression—a role that has not been fully appreciated until now.  

Borchert's lab, which has received funding from the National Science Foundation, is continuing to explore the role of LG4s in gene regulation. The team has requested additional funding to further investigate how these DNA structures could be harnessed for therapeutic applications and to better understand their potential impact on diseases linked to gene expression.  

“We believe DNA-based regulations like the one we've described in this publication constitute major hitherto undescribed mechanisms coordinating human gene expression,” he said, “and their exploration will provide significant new insights into normal human gene expression and disease moving forward.”  

Read the new study in Nucleic Acids Research.