Quantitative dissection of transcription in development yields evidence for transcription-factor-driven chromatin accessibility.

Cells in the brain, liver and skin, as well as many other organs, all contain the same DNA, yet behave in very different ways. This is because before a gene can produce its corresponding protein, it must first be transcribed into messenger RNA. As an organism grows, the transcription of certain genes is switched on or off by regulatory molecules called transcription factors, which guide cells towards a specific 'fate'. These molecules bind to specific locations within the regulatory regions of DNA, and for decades biologist have tried to use the arrangement of these sites to predict which proteins a cell will make. Theoretical models known as thermodynamic models have been able to successfully predict transcription in bacteria. However, this has proved more challenging to do in eukaryotes, such as yeast, fruit flies and humans. One of the key differences is that DNA in eukaryotes is typically tightly wound into bundles called nucleosomes, which must be disentangled in order for transcription factors to access the DNA. Previous thermodynamic models have suggested that DNA in eukaryotes randomly switches between being in a wound and unwound state. The models assume that once unwound, regulatory proteins stabilize the DNA in this form, making it easier for other transcription factors to bind to the DNA. Now, Eck, Liu et al. have tested some of these models by studying the transcription of a gene involved in the development of fruit flies. The experiments showed that no thermodynamic model could accurately mimic how this gene is regulated in the embryos of fruit flies. This led Eck, Liu et al. to identify a model that is better at predicting the activation pattern of this developmental gene. In this model, instead of just 'locking' DNA into an unwound shape, transcription factors can also actively speed up the unwinding of DNA. This improved understanding builds towards the goal of predicting gene regulation, where DNA sequences can be used to tell where and when cell decisions will be made. In the future, this could allow the development of new types of therapies that can regulate transcription in different diseases.