In a groundbreaking discovery, researchers have uncovered a previously unknown “spatial grammar” code within DNA that is key to understanding how gene activity is encoded in the human genome. This finding, published in Nature’s prestigious journal, could revolutionize scientists’ comprehension of gene regulation and how genetic variations influence gene expression during development and disease.
The research, conducted by a team from Washington State University and the University of California, San Diego, reveals that the function of transcription factors — the proteins that control which genes are turned on or off — is far more complex than previously believed. Contrary to the textbook understanding of transcription factors as simple activators or repressors, the scientists found that most can serve in both capacities.
“It just goes to show that similar to learning a new language, to learn how gene expression patterns are encoded in our genome, we need to understand both its words and the grammar,” said Sascha Duttke, an assistant professor at WSU’s School of Molecular Biosciences and the lead author of the study.
The key to this newfound “spatial grammar” lies in positioning transcription factors relative to a gene’s transcription start site. The researchers discovered that the spacing and location of these regulatory proteins determine whether they will activate or repress a gene’s expression.
“If you remove an activator, your hypothesis is you lose activation,” explained Bayley McDonald, a WSU graduate student on the research team. “But that was true in only 50% to 60% of the cases, so we knew something was off.”
Further investigation revealed that transcription factors can act as activators when positioned upstream of a gene’s start site, but switch to become repressors when located downstream. This “ambience,” or spatial arrangement, ultimately dictates the transcription factor’s function.
“The potential applications are vast,” said Christopher Benner, an associate professor at UC San Diego. “At the very least, it will change the way scientists study gene expression.”
By incorporating this newly unveiled “spatial grammar” into their research, scientists anticipate gaining deeper insights into how genetic variations and mutations can affect gene expression, potentially leading to breakthroughs in understanding and treating a wide range of diseases.
“This breakthrough finding revealed a long-postulated hidden spatial grammar embedded in DNA,” the researchers stated. “The research could reshape scientists’ understanding of gene regulation and how genetic variations may influence gene expression in development or disease.”
