A newly discovered code in DNA – the so-called ‘spatial grammar’ – holds a key to understanding how gene activity is coded in the human genome.
This groundbreaking finding, identified by researchers at Washington State University and the University of California, San Diego and published in Naturerevealed a long-postulated hidden spatial grammar embedded in DNA. The research could reshape scientists’ understanding of gene regulation and how genetic variations can influence gene expression in development or disease.
Transcription factors, the proteins that determine which genes in a person’s genome are turned on or off, play a crucial role in this code. This research, long seen as activators or repressors of gene activity, shows that the function of transcription factors is much more complex.
“Contrary to what you find in textbooks, transcription factors that act as true activators or repressors are surprisingly rare,” says WSU Assistant Professor Sascha Duttke, who led much of the research at WSU’s School of Molecular Biosciences in the College of Veterinary Medicine.
On the contrary, the scientists discovered that most activators can also function as repressors.
“If you remove an activator, your hypothesis is that you lose activation,” says Bayley McDonald, a WSU graduate student who was part of the research team. “But that was only true 50% to 60% of the time, so we knew something was wrong.”
Upon closer inspection, researchers found that the function of many transcription factors was highly position dependent.
They found that the distance between transcription factors and their position relative to where a gene’s transcription began determined the level of gene activity. For example, transcription factors can activate gene expression when placed upstream or before the site where transcription of a gene begins, but inhibit its activity when located downstream or after the start site of a gene’s transcription.
“It is the space, or ‘sphere,’ that determines whether a given transcription factor acts as an activator or a repressor,” Duttke said. “It just goes to show that, just like learning a new language, to learn how gene expression patterns are encoded in our genome, we need to understand both the words and the grammar.”
By integrating this newly discovered “spatial grammar,” Christopher Benner, associate professor at UC San Diego, expects scientists can gain a deeper understanding of how mutations or genetic variations can affect gene expression and contribute to disease.
“The potential applications are enormous,” Benner said. “At the very least, it will change the way scientists study gene expression.”
