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Fingerprinting Small Molecule Modulators of Nucleolar Biophysics

Ribosomal RNA (rRNA) is the most abundant RNA in cells, reflecting its fundamental role in enabling protein synthesis in all living organisms. Nucleolus is a membraneless and multicompartmentalized nuclear body that governs rRNA biogenesis, a process that is misregulated in various diseases. Recent research has identified several small molecule therapeutics that alter rRNA biogenesis and subsequently nucleolar morphology, challenging the accepted mechanisms of action for these compounds and simultaneously establishing the nucleolus as an attractive therapeutic target. Nevertheless, there are currently no comprehensive and quantitative frameworks that capture and relate various drug‐induced changes in nucleolar morphology and its material properties to its function. We hypothesized that we can establish such a structure‐function framework by screening a panel of nucleolus‐perturbing small molecule drugs and measuring changes in biophysical properties of the nucleolus in cells from microscopy images. Here, we combine morphometric, thermodynamic, and kinetic measurements of drug‐treated nucleoli to reveal “fingerprints” for drugs that modulate distinct stages of rRNA biogenesis. We anticipate that this framework provides a starting point for robustly determining and predicting structure‐function relationships for nucleolar phenotype perturbations as well as for developing high‐content screening platforms to expedite the discovery of novel nucleolus‐targeting therapeutics.