COMPOSITION-DEPENDENT CONTROL OF NUCLEOLI AND NUCLEOLAR-DERIVED CONDENSATES

About This Grant

Eukaryotic cells coordinate numerous biochemical reactions within specialized liquid-like compartments known as condensates. The largest of these, the nucleolus, has been proposed to orchestrate ribosome biogenesis by enhancing and regulating the dynamics of relevant molecules and their reactions. Consequently, nucleolar form (size, shape, and fluidity) and ribosome biogenesis are frequently disrupted in human diseases like developmental and neurodegenerative disorders, cancer, and aging. More generally, a persistent issue is the physical principles that govern the structure and function of condensates in cells and their relationship to liquid-liquid phase separation, akin to how oil droplets form in water. Indeed, nucleoli are complex structures formed through the interactions of numerous proteins and RNA, regulated by various aspects of cellular biology, which recent models must adequately address. My laboratory aims to develop new quantitative methods to clarify the physical properties and principles of condensates in cells, thereby enhancing our understanding of their role in cellular processes. We are investigating the hypothesis that phase separation and the formation of a nucleolar meshwork affect biomolecular transport and the rate of ribosome biogenesis, which the cell can subsequently regulate and may be compromised in disease. Recently, we have developed a novel quantitative microscopy method to determine the local meshwork and structure within condensates on the nanometer scale. Here, we seek to determine if there are changes in the composition of the nucleolus and nucleolar-derived condensates in response to cellular stimuli and during cellular transitions. We anticipate that addressing this question will uncover new biophysical principles underlying nucleolar form and the relationship between form and function, which may have broad implications for understanding and investigating the molecular mechanisms of condensate action in human physiology and disease.