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

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Life begins with a cell. When an organism develops, the dividing cells specialize to form the variety of tissues and organs that make up the adult body, while retaining the same genetic material, contained in our DNA. In a process known as transcription, parts of DNA – genes – are copied into a messenger molecule – ribonucleic acid (RNA) – which carries information needed to produce proteins, the building blocks of the life. The parts of our DNA that are read and transcribed determine the fate of our cells. DNA readers are proteins called transcription factors: they bind to specific sites in DNA and activate the transcription process. How they recognize where in the DNA they should bind and how these are distinguished from other random binding sites in the genome remains an open question. Scientists from the Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG) and the Max Planck Institute for Physics of Complex Systems (MPI-PKS), both located in Dresden, show that thousands of factors individual transcripts associate and interact with each other. They collectively wet the DNA surface by forming liquid droplets that can identify clusters of binding sites on the DNA surface.

Transcription, one of the most fundamental cellular processes, is the action by which the information contained in DNA is transcribed into RNA, the messenger molecule. This “message” is then translated into proteins. Deciding which parts of DNA are transcribed at any given time is crucial for proper development to maintain the health of an organism, as many diseases are likely to arise when genetic programs are not executed correctly. The decision about which genes to transcribe is made by a complex network of regulatory proteins called transcription factors. Although these factors bind to short DNA sequences, recognition of clusters of many such sequences is required to activate neighboring genes.

The research groups of Stephan Grill and Anthony Hyman, both directors at MPI-CBG, and the group of Frank Jülicher, director at MPI-PKS investigated in their recent study in the journal Natural Physics how transcription factors find and recognize clusters of many specific DNA sequences where they can bind and lead to gene activation. To find 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 used optical tweezers – a technology that uses lasers to isolate and manipulate very small objects such as single DNA molecules – combined to confocal microscopy to observe them individually With optical tweezers it is possible to capture a single molecule of DNA and with confocal microscopy we can observe transcription factors binding and forming protein condensates to their sequences The fact that we can study this process one molecule at a time has allowed us to detect interactions otherwise muddled by the complexity of the living cell.” Sina Wittmann, another first author, adds: “With the help of physicists, we were able to understand how transcription factors communicate with each other and assemble through teamwork. They undergo what is called a pre-wetting transition to form liquid-like droplets, which resemble 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 the DNA sequence.

Stephan Grill summarizes: “We now have a possible mechanistic explanation for the localization of transcription factors along the genome. This is essential for understanding how gene expression is regulated. Knowing that this regulation breaks down in developmental diseases and cancer, these new results provide a better understanding of how these diseases arise. This knowledge is important to think about new therapeutic options taking into account the teamwork of transcription factors.

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Materials provided by Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG). Note: Content may be edited for style and length.

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