USA Awarded NSF Grant to Study Role of Enhancer DNA Sequences in Gene Expression
MOBILE, Ala. (Oct. 6, 2022) – The National Science Foundation has awarded the University of South Alabama a $427,000 grant to better understand enhancer DNA sequences and their role in coordinating gene expression.
Promoters and enhancers are both noncoding sequences of DNA that serve as gene-regulatory elements. Promoters initiate gene transcription, which is the first step in gene expression, the “turning on” of a gene. Enhancers increase the level or speed up the rate of transcription.
“Interestingly, numerous genome-wide association studies attempting to link genomic mutations with various traits and/or diseases have repeatedly found that more than 90% of disease-associated mutations lie within the noncoding portions of the genome,” said Glen Borchert, Ph.D., associate professor of pharmacology at the Frederick P. Whiddon College of Medicine. “Even more strikingly, most of these mutations lie within regions of the genome thought to function as enhancers rather than promoters.”
A promoter is a region of DNA upstream of a gene where proteins bind to initiate transcription of a gene by producing an RNA copy of the gene sequence. Borchert, who is principal investigator of the project, said, “Promoters can be very complex and typically work together with other DNA regions known as enhancers to ensure specific, robust gene transcription.”
Despite their complexity, promoters are readily identifiable, as they generally correspond to the 100 to 1,000 base pairs (bp) immediately upstream of a gene. “This has allowed a massive number of detailed promoter characterizations to be performed, stretching back decades,” Borchert said.
Enhancer characterizations, however, have proven much more challenging. Like promoters, enhancers are typically short 100 to 1,000 bp DNA sequences that serve to markedly upregulate gene transcription; but, unlike promoters, an enhancer can be found up to 1 million bp away from the gene it influences.
“How do enhancers work across such large distances? In short, genomic DNA bends, bringing an enhancer and promoter in close proximity to initiate transcription,” Borchert explained.
“Despite their importance, to date, we still have a very limited ability to define enhancer sequences,” he said, “and major gaps in our understanding of their mechanisms of action and targeting determinants remain unanswered.”
Understanding what drives this interaction between promoters and enhancers can significantly improve our ability to treat diseases caused by gene mutations or improve crop resistance to adverse environmental conditions via gene modulation, Borchert said.