Transcription factor position determines gene activity

'Spatial grammar' within our DNA code has been uncovered, which could change our understanding of how genes are activated.

Gene activity and expression is controlled by proteins called transcription factors that bind to DNA sequences and have traditionally been known to act solely as activators or repressors of genes. However, researchers from Washington State University and the University of California, San Diego, published a paper in Nature revealing a new level of complexity. It is the 'spatial grammar' within the DNA – the positioning of the proteins relative to the genetic code – that determines whether transcription factors act as activators or repressors to regulate gene expression.

This concept was described by Dr Sascha Duttke, assistant professor from Washington State University, who was first author of the study: '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.'

The discovery was made when researchers noticed contradictions to the traditional view of how transcription factors performed. Scientists previously believed that removing an activator would stop gene activation, but this was only true in 50-60 percent of the cases studied.

Upon further investigation, researchers found that the function of transcription factors was largely position-dependent and influenced by more than one dimension. The spacing between transcription factors and their position relative to where gene transcription begins significantly affected gene activity.

For instance, if a transcription factor is located before the start site of gene transcription, it might activate gene expression. However, if the transcription factor is located further downstream, beyond the transcription start site, it may act to prevent gene expression.

This refinement in transcription factor behaviour could reform our understanding of gene expression and, in turn, enable scientists to more effectively investigate its contribution to health and disease.

Senior author Dr Christopher Benner, associate professor at the University of California, San Diego, highlighted: 'The potential applications are vast. At the very least, it will change the way scientists study gene expression.'