Investigating the role of biomolecular condensates in post-transcriptional gene regulation

• Applicant: Daniel Mateju, Ph.D.
• Subject Area: Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506619116

Post-transcriptional regulation of gene expression requires the action of RNA-binding proteins (RBPs) that bind to specific mRNA molecules in order to modulate mRNA processing, localization, translation, and stability. Furthermore, multivalent interactions between RBPs and mRNA molecules can lead to the formation of larger ribonucleoprotein (RNP) condensates and granules – a class of membraneless organelles that consist of RNA and proteins. Some types of RNP condensates are present in most cell types (e.g., paraspeckles), while others form only in specific cell types (e.g., neuronal transport granules) or form transiently in response to environmental stimuli (e.g., stress granules). Recent studies have provided insight into how RNP condensates form and how are they regulated. It has also become clear that RNP condensates play key roles in diseases including neurodegeneration, cancer, and viral infections. However, it remains largely unclear how these organelles affect mRNA metabolism and what are the functional consequences of RNA-protein condensation. In this project, we will address three major questions: How are mRNAs affected by incorporation into RNP condensates and granules? How do different types of RNP condensates affect each other? How is the function of RNP condensates impacted by disease-causing mutations in RBPs? Tackling these questions will require the use of new techniques to directly measure the biological processes occurring inside the RNP condensates, as well as targeted approaches to manipulate these organelles. Here we will focus on multiple types of RNP condensates involved in cellular stress response, cell adhesion, and in mRNA transport. We will apply RNA-tagging tools and single-molecule imaging methods to investigate the functional consequences of mRNA recruitment into RNP condensates. This will be combined with other imaging-based techniques as well as sequencing-based experiments. The project results will provide new mechanistic insights into cellular compartmentalization and post-transcriptional gene regulation, and further help us understand the role of RNP condensates in pathological conditions, such as neurodegenerative disorders that are caused by mutations in granule-forming RBPs.

• DFG Programme: Independent Junior Research Groups