Cells are defined by the genes they express. In human cells, there are thousands of different protein coding genes, and the expression of those genes is carefully orchestrated and controlled by a variety of elements, including molecules known as transcription factors. Those factors may enhance or reduce gene activity, and they may be turned on or off at different times. But these transcription factors can have a very complex influence on gene expression that is more than just a simple increase or decrease in activity. A new study has shown that a transcription factor's influence on gene expression depends on the position where the transcription factor binds to DNA. The findings have been reported in Nature, and they may have major implications for our understanding of basic aspects of biology and disease, the researchers noted.
"Contrary to what you will find in textbooks, transcription factors that act as true activators or repressors are surprisingly rare," said co-corresponding study author and Washington State University (WSU) assistant professor Sascha Duttke.
It seems that most transcription factors that work as activators of gene expression can also have a repressive effect, and their effect was shown to be dependent on position.
"If you remove an activator, your hypothesis is you lose activation," said study co-author Bayley McDonald, a WSU graduate student. But the investigators determined that only happens in about half of the cases. They wanted to learn more about what was happening.
The spacing of transcription factors and the place where a gene is first transcribed by the cellular machinery was found to determine how the transcription factor affected gene activity. Transcription factors that were positioned before the start site could have a boosting effect on gene expression, but if they bound after that start site, they could repress, for example.
"It is the spacing, or 'ambience,' that determines if a given transcription factor acts as an activator or repressor," Duttke said. "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."
This is a kind of 'spatial grammar' of gene expression that may help researchers reveal new details about the impact of different genetic mutations or variants, noted co-corresponding study author Christopher Benner, an associate professor at University of California, San Diego.
"The potential applications are vast," Benner said. "At the very least, it will change the way scientists study gene expression."
Sources: Washington State University, Nature