How liquid-like protein droplets collectively read DNA regions to switch on genes

Transcription, one of the most fundamental cellular processes, is the action by which the information contained in the DNA is transcribed into the messenger molecule RNA. This "message" is later translated into proteins. Deciding which parts of the DNA are transcribed at any given moment is crucial for proper development to maintain the health of an organism, because many diseases are likely to occur when the genetic programs are not executed correctly. The decision as to which genes are transcribed is made by a complex network of regulatory proteins called transcription factors. While these factors bind to short DNA sequences, the recognition of clusters of many such sequences is required to switch on nearby genes.

The research groups of Stephan Grill and Anthony Hyman, both directors at the MPI-CBG, and the group of Frank Jülicher, director at the MPI-PKS investigated in their recent study in the journal Nature Physics how transcription factors find and recognize clusters of many specific DNA sequences where they can bind and lead to gene activation. To find this out, the researchers followed an interdisciplinary approach, combining expertise in experimental and theoretical biophysics with cell biology. Jose A. Morin, one of the first authors of the study, explains: "We employed optical tweezers -- a technology that uses lasers to isolate and manipulate very small objects such as single DNA molecules -- combined with confocal microscopy to look at them individually. With optical tweezers it is possible to capture a single DNA molecule and with confocal microscopy we can observe transcription factors binding and forming protein condensates at their preferred DNA sequences. The fact that we can study this process one molecule at the time allowed us to detect interactions otherwise blurred by the complexity of the living cell." Sina Wittmann, another first author, adds: "With the help of the physicists, we were able to understand how transcription factors communicate with each other and assemble through team work. They undergo what is called a prewetting transition to form liquid-like droplets, which are similar to the drops on a mirror in your bathroom after a shower. These condensates are filled with thousands of transcription factors. Assembled in this way, the transcription factors can now identify the correct DNA region by reading out DNA sequence."

Stephan Grill summarizes: "We now have a possible mechanistic explanation for the localisation of transcription factors along the genome. This is essential to understand how gene expression is regulated. Since we know that this regulation breaks down in developmental diseases and cancer, these new results give us a clearer picture of how these diseases occur. This knowledge is important to think about new therapeutic options that take the team work of transcription factors into account."