TRANSCRIPTION AND NUCLEAR PHASE TRANSITIONS

This project aims at connecting via an interdisciplinary approach two phenomena that are of fundamental importance in biology and medicine.

The first one is transcription, the production of messenger-RNAs (mRNAs) from genes on the DNA. mRNAs are used by cells to make proteins, the main components for function and growth of cells. Understanding function and regulation of transcription is therefore of critical importance for comprehensive insights into cellular function in health and disease. Yet, many aspects of transcription remain unclear and are challenging to study due to the contributions of the second phenomenon we want to study, the dynamical turnover of a certain type of 'clusters' in the nucleus of a cell.

This clustering appears to involve various different proteins, many of which are implicated in transcriptional regulation, and possibly includes DNA and mRNA. This phenomenon was discovered only recently and appears to relate to the regulation of transcription, although mechanistic details are elusive. Apart from its role in transcription, clustering of proteins is a hallmark of neurogenerative diseases, which mandates a better understanding of its functional purposes.

While research in transcription is a biological venture, studying clustering requires a physics approach; the clusters form relatively large structures in the nuclei, which are akin to phase changes that are seen when a liquid substance becomes solid or vice versa. This results in unique biophysical properties within the clusters that are not amenable to biology-based research strategies.

Our goal in this project is to form an interdisciplinary team of physicists, biologists, and mathematicians to investigate the nature of the interactions between clusters and transcription. This provides a chance to explain and unify these two phenomena in a mechanistic sense, along with prospects to include and thus understand many other unexplained biological observations. The biological side of our team will provide expertise and methodology for investigating transcription and its dynamics and for locating important proteins on and alongside DNA and mRNAs. The physicists will investigate the properties of the clusters and their interactions with other objects in the cells' nuclei using advanced microscopic imaging techniques and modelling approaches, with input from mathematicians. The different strands of work in the project will be very strongly integrated to maximize the interdisciplinary exchange and facilitate the emergence of novel insights.

The project will significantly advance our understanding of fundamental processes in human biology, with the associated strong medical implications. It will also contribute to the creation of long-term collaborative arrangements between researchers in different disciplines.

Publication and presentation of our findings at meetings will make them available to the research community and will therefore advance the general understanding of the interplay of transcriptional dynamics, nuclear phase transitions, and polymer physics.

We are planning to attend the 23d International Conference on Systems Biology (ICSB) in 2021 and a number of smaller national conferences in physics and/or biology throughout the length of the project.

Dissemination of our research will also be strong among the synthetic biology and cell biology communities. One of the principal investigators (Hebenstreit) is a founding member of the EPSRC/BBSRC Warwick Integrative Synthetic Biology Centre (WISB). WISB is one of six UK Synthetic Biology Research Centers recently established by BBSRC and EPSRC, and as such is highly networked in the synthetic biology research landscape both nationally and internationally. The second principal investigator is a member of the Warwick Centre for Mechanochemical Cell Biology (CMCB), which is interdisciplinary by design and has ties to

In accordance with the EPSRC requirements, all publications will be open-access, which will help to distribute our findings to a wide audience, thus maximizing impact. In addition, depending on the details of our outcomes, we will further consider journals that cover a wider range of topics, thus ensuring impact outside of our immediate research field. This includes the fields of methods development, polymer physics, genomics, statistics, structural biology, and stochastic modelling.

The data we generate and the processing and analysis routines we will develop will provide other researchers with key starting points for further analyses. This will be particularly relevant for the genomics community as the field largely relies on publicly available datasets. To facilitate this, we will make our data freely accessible on repositories as explained in the data management plan. Neurobiologists will profit from our research as well, as it will improve understanding of the function and properties of protein aggregation in the nucleus, which in turn will also benefit medical research.

The project will be carried out by four postdoctoral researchers and will be complemented by two PhD students the University has committed to. The researchers will work at the interface of molecular biology and physics. This provides for an excellent training environment for the researchers, who will jointly use a wide variety of approaches, including mathematical modelling, next generation sequencing, Cas9 targeting, statistics single molecule experimental techniques (smFISH), programming (Python, R) and others. The University of Warwick further provides a broad range of courses aimed at training in systems biology which the researcher will be encouraged to participate in. The postdoctoral researchers will thus obtain state-of-the-art interdisciplinary training, which will be highly valuable in light of the upcoming scientific challenges. We will further strongly encourage the researchers to engage in professional development, which the University of Warwick also offers several courses for, such as 'Introduction to Networking', 'Research Team Leadership Programme', the 'Academic Writing Bootcamp', as well as 'Working with International Students'. Further development opportunities for the postdoctoral researchers include participation in outreach activities as explained in the Pathways to Impact.