All life begins with one cell. During the development of an organism, cells divide and become specialized, yet each cell nucleus contains the same hereditary material. Our DNA is tightly packed to fit into the nucleus of every cell. From our genetic library, products like RNA and proteins are made and they serve as molecular machines and structural components for many processes happening inside our cells. The first step towards these products is a process called transcription, by which the instructions in our DNA are used to construct a functional product. So far it was not clear how places for transcription activity in the cell nucleus are established. The international collaborative research team of the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), the Max Planck Institute for the Physics of Complex Systems (MPI-PKS) and the Center for Systems Biology (CSBD), all located in Dresden, together with Tokyo Institute of Technology in Japan, led by Nadine Vastenhouw and Vasily Zaburdaev, now found how the genetic material gets organized into active and inactive pockets within the nucleus, how those pockets for transcription are established and how this pattern can be explained by a physical model.
In eukaryotes, the genetic material stored in DNA is packaged inside cell nuclei. In a process known as transcription, which also happens in nuclei, pieces of DNA are copied and transcribed into RNA, or transcript, that carries the information needed to build a protein. Transcription is a basic cellular process in gene expression and requires tight control to produce functional products at the appropriate place and time for proper cell function and development of an organism. It has been known for a long time that there are defined areas in the nucleus containing either transcriptionally active or inactive DNA. However, it was unknown so far how the genetic material, the DNA, is being sorted into active and inactive areas and how those areas of gene expression activity are established.
An international research team from the MPI-CBG, the MPI-PKS, the CSBD and the Tokyo Institute of Technology in Japan worked together to investigate this unsolved question and published their results in the journal Nature Communications. They took an interdisciplinary approach, combining cutting-edge super-resolution microscopy and theoretical models that allowed the researchers to go deep into the zebrafish cell nucleus and observe DNA and RNA transcripts in time and nuclear space during the transcription process. They saw that the DNA, which is initially evenly distributed in the cell nucleus, established a finely structured pattern in the nucleus with the appearance of RNA transcripts. Nadine Vastenhouw, who supervised the study explains: “When the cell goes from a state of no transcription activity to an active state, we saw distinct areas of highly compacted DNA. In addition, we also saw pockets with almost no DNA which were instead occupied with RNA that was created during transcription. This emerging pattern means that the RNA made through transcription can organize DNA into an “active” pocket, such that inactive DNA is pushed out.” The transcription process prevented the full separation of these pockets though. Vasily Zaburdaev, the co-supervising author and now located at the Friedrich-Alexander-Universität Erlangen-Nürnberg and the Max-Planck-Zentrum für Physik und Medizin, adds: “To us it looked as if DNA and RNA tried to avoid each other, just like water and oil do not like to mix. The two phases are connected by the active DNA. Just like soap added to a mixture of oil and water would cause the formation of multiple small bubbles, known as an emulsion.”
The first author of the study, Lennart Hilbert, was formerly a postdoctoral researcher in the groups of Nadine Vastenhouw (MPI-CBG) and Vasily Zaburdaev (MPI-PKS) and is now located at the Karlsruhe Institute of Technology (KIT). He explains: “Our work, in the language of theoretical physics, now could explain how the cell nucleus sorts active and inactive genes into different compartments, a phenomenon known to cell biologists for several decades. The collaborative environment at the Dresden institutes was decisive in this endeavor, allowing us to apply some of the most advanced microscopy techniques to zebrafish embryos, and combine them with biophysical model simulations.”
Nadine Vastenhouw, now located at the University of Lausanne in Switzerland, gives an outlook: “Transcription is a fundamental process in biology. To ensure that our genome is properly read and the right products are made, the genome and the machinery needed at each step have to be highly organized in nuclear space. Our study provides an important step towards understanding how DNA and transcription activity is organized, so that the appropriate products are made, cells take up the right fate and collectively become the right tissue, and the organism can develop normally.”
Lennart Hilbert, Yuko Sato, Ksenia Kuznetsova, Tommaso Bianucci, Hiroshi Kimura, Frank Jülicher, Alf Honigmann, Vasily Zaburdaev, &, Nadine L. Vastenhouw: “Transcription organizes euchromatin via microphase separation”, Nature Communications, 01. March 2021.