New discovery could rewrite genetics textbooks

Researchers discover ‘spatial grammar’ in DNA This redefines the role of transcription factors in gene regulation, impacting our understanding of genetic changes and diseases.

The discovery of a new code within DNA, known as a “spatial grammar,” may help us unlock the secret behind how gene activity is encoded in the human genome.

This groundbreaking discovery, made by researchers at Washington State University and the University of California, San Diego and published in the journal natureA new study has uncovered a long-hypothesized hidden spatial grammar in DNA. The research could reshape scientists’ understanding of gene regulation and how genetic variations might influence gene expression during development or disease.

Discovering positional dependency

Transcription factors, proteins that control which genes are turned on or off in the genome, play a crucial role in this code. Long thought to act as either activators or repressors of gene activity, this research shows that the function of transcription factors is much more complex.

“Contrary to what you’ll find in textbooks, transcription factors that act as true activators or repressors are surprisingly rare,” said Sascha Dutke, an assistant professor at Washington State University who led most of the research in the College of Veterinary Medicine’s School of Molecular Biosciences.

Instead, scientists have found that most stimulants can also act as inhibitors.

“If you remove the activator, your hypothesis is that you lose the activation,” said Bailey MacDonald, a graduate student at Washington State University who was part of the research team. “But that was only true 50 to 60 percent of the time, so we knew something was wrong.”

Taking a closer look, the researchers found that the function of many transcription factors is highly dependent on location.

Researchers have discovered that the distance between transcription factors and their location relative to the gene transcription start site determines the level of gene activity. For example, transcription factors may activate gene expression when placed upstream or in front of the gene transcription start site, but inhibit its activity when placed downstream, or after the gene transcription start site.

“It is the spacing, or ‘environment,’ that determines whether a particular transcription factor acts as an activator or a repressor,” Dutke said. “This shows that, similar to learning a new language, to learn how gene expression patterns are encoded in our genome, we need to understand its words and grammar.”

Implications for genetic research

Christopher Benner, an assistant professor at the University of California, San Diego, expects that by incorporating the newly discovered “spatial rules,” scientists will be able to gain a deeper understanding of how mutations or genetic variations affect gene expression and contribute to disease.

“The potential applications of this technology are enormous,” Benner said. “At the very least, it will change the way scientists study gene expression.”

Reference: “Position-dependent function of human sequence-specific transcription factors” by Sascha H. Dutke, Carlos Guzman, Max Chang, Nathaniel P. Delos Santos, Billy R. McDonald, Jia-Li Shi, Aaron F. Karlin, Sven Heinz, and Christopher Benner, July 17, 2024. nature.
doi: 10.1038/s41586-024-07662-z