Extracellular Adhesive Cues Physically Define Nucleolar Structure and Function

Adhesive cues from the extracellular matrix (ECM) specify the size and shape of the nucleus via mechanical forces transmitted through the cytoskeleton. However, the effects of these biophysical stimuli on internal nuclear architecture and cellular responses remain poorly understood. This study investigates the direct impact of ECM adhesion on nucleolar remodeling in human keratinocytes using micropatterned substrates. Limited adhesion on small micropatterns promotes fusion of nucleoli, alongside a reduction in nuclear volume and condensation of heterochromatin. These changes in nucleolar architecture are mediated by altered chromatin biomechanics and depend on integration of the nucleus with the actin cytoskeleton. Functionally, nucleolar remodeling regulates ribogenesis and protein synthesis in keratinocytes and is associated with specific transcriptional changes in ribogenesis genes. Together, these findings demonstrate that cell shape and nuclear morphology control nucleolar structure and function and implicate the nucleolus as a key mechano-sensing element within the cell.