How do transcription factors switch on genes?

A new analysis of existing microscopy data suggests that the way transcription factors bind to DNA may be more complex than previously thought.
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The bodies of humans and other animals contain many types of cells that perform different roles in the body. Most cells in the body carry the same DNA, which is arranged into sections known as genes. The marked differences between cell types arise because different sets of genes are switched on or ‘expressed’.

Proteins called transcription factors control which genes are expressed by binding to DNA and recruiting groups of accessory proteins. However, it is not clear how they interact with each other and with the accessory proteins to decide whether to express a gene. For instance, it is thought that some accessory proteins may provide energy for this process, but it is unknown whether the energy is used continuously or only for a short time. Insights from physics suggest that the former could have more powerful effects.

In 2014, a team of researchers reported using a microscopy approach, known as single-molecule imaging, to follow two transcription factors called Sox2 and Oct4 in cells from mice. After analyzing the data, the researchers concluded that Sox2 and Oct4 had a specific order of binding to DNA, with Sox2 often binding first and then assisting Oct4 to bind. Now Biddle et al. report that the claim made in the 2014 study is unsupported because of errors in the way the data were analyzed. In particular, Biddle et al. argue that what the earlier study actually calculated is not an order of binding but a measure of whether energy is being continuously used when Sox2 and Oct4 bind to DNA.

Biddle et al. reanalyzed the data from the 2014 work and concluded that Sox2 increases the extent of Oct4 binding to DNA, while Oct4 decreases the amount of Sox2 binding to DNA. Mathematical models suggest this may be due to the continuous use of energy as the two proteins bind to DNA. Alternatively, it could also happen if Sox2 and Oct4 helped each other to bind at some sites on DNA and hindered each other from binding in other places, even if energy is only used for a short time. These findings reveal that there is unexpected complexity in how transcription factors bind to DNA.

The next step following on from this work is to carry out experiments that test the two possible explanations for how Sox2 and Oct4 interact on DNA. Including physics in the analysis may help describe more accurately the biology of how transcription factors determine gene expression. Understanding this process will shed new light on many important biological questions and may aid the development of gene therapy and other new medical techniques.