It is common knowledge that for doing a job right, one requires the right tools. Each cell in the body has a particular job or function; for instance, pancreatic cells have to produce insulin, whilst cells in the eye’s retina have to sense light and color. The right ‘tools’ for cells are proteins encoded by genes, i.e. the ‘right’ genes for the job are only turned on in particular cells where they are needed. However, just as using the wrong tool for the job can end up in disaster, the same applies if the wrong genes are turned on in a cell.

Scientists have known for years that turning on the wrong genes can, in some cases cause serious illnesses, including cancer. They also know that transcription factors, i.e. specific proteins that are either turned on or off in cells, depending on whether they do or don’t bind to nearby DNA, act just like a switch, whereby ‘on’ means they bind to DNA and ‘off’ they don’t.

According to a study published in the April 12 issue of Nature, UNC-led team of scientists, transcription factors do not act like an ‘on-off’ switch, their binding behavior is in fact considerably more complex.

Professor Jason Lieb, PhD, senior author of the study and a member of UNC Lineberger Comprehensive Cancer Center, explains:

“This is a new way of looking at how genes are controlled. For a while now there have been molecular maps that show the location of where the proteins are bound to DNA – like a roadmap. For the first time, we are able to show the molecular equivalent of a real-time traffic report.”

When working with yeast, the UNC team discovered that the transcription factors’ binding process involves more than being bound to DNA or not, it is dynamic and can ‘treadmill’, meaning no forward transcription process occurs. The team hypothesizes that within this process, there may be a molecular “clutch” that converts ‘treadmilling’ to a stable bound state, and then moves the transcription process forward to complete turning on the gene.

Lieb, who is also director of the Carolina Center for Genome Sciences, explains:

“This discovery is exciting because we developed a new way to measure and calculate how long a protein is associated with all of the different genes it regulates. This is important because it represents a new step in the process of how genes are regulated. And with every new step, there are opportunities for new mechanisms of regulation. We found that proteins that bind in the stable state are associated with high levels of gene transcription. We think that if we can regulate the transition between ‘treadmilling’ and stable binding, we can regulate the outcome in terms of gene expression. Ultimately, this type of regulation could be important for genetic medicine – a new way to regulate the ‘switches’ that turn gene expression associated with disease on or off.”

The researchers decided to conduct a controlled competition between two copies of the same transcription factor that each had a unique molecular tag. They allowed one of the proteins to bind to all of its gene targets before introducing the second copy, and measured the time it took for the resident protein to be replaced with the competitor transcription factor. They then used this information to calculate the residence time at each location in the genome.

Colin Lickwar, MS, first author of the paper, comments:

“We didn’t know if the residence time was important, but we found that the residence time was a much better indicator of whether a gene was turned on or off than previous measures of binding.” Anthony Carter, PhD, from the National Institutes of Health’s National Institute of General Medical Sciences, explains, “By taking an interdisciplinary approach that incorporates the use of mathematical modeling tools, Dr. Lieb has shed new light on a fundamental cellular process, the ability to quickly shift between active and inactive states of gene expression. The findings may offer new insights on how cells respond to developmental cues and how they adapt to changing environmental conditions.”

Written By Petra Rattue