Biophysical Society Thematic Meeting | Singapore

Mechanobiology of Disease

Poster Abstracts

32-POS Board 32 Cytoskeleton-medicated Nuclear Mechanics : Mechanobiological Approach into the Subcellular Nanomachinery Dong-Hwee Kim 1 , Sun X. Sun 2 , Denis Wirtz 3 . 1 Korea University, Seoul, South Korea, 2 Johns Hopkins University, Baltimore, MD, USA, 3 Johns Hopkins University, Baltimore, MD, USA. Alterations in nuclear morphology are closely associated with essential cell functions and correlate with a wide range of human diseases, including cancer, muscular dystrophy, dilated cardiomyopathy and progeria. However, the mechanics and forces that shape the nucleus are not well understood. Accumulating evidence suggests that the three-dimensional organization of the nucleus regulates gene expression through lamina-chromosome interactions. The nuclear lamina is a thin filamentous meshwork that provides mechanical support to the nucleus and regulates essential cellular processes such as DNA replication, chromatin organization, cell division, and differentiation. Conventional microscopy has long suggested that the nuclear lamina is composed of structurally different intermediate filamentous lamin proteins and nuclear lamin-associated membrane proteins that together form a thin shell largely confined to a narrow region underneath the nuclear envelope. Here we show that both A-type lamins and transcriptionally active chromatins are vertically polarized by the tension exercised by the perinuclear actin cap that is composed of highly contractile actomyosin fibers organized at the apical surface of the nucleus. Furthermore, we first demonstrate that the nucleus undergoes a large volumetric reduction accompanied by a morphological transition from an almost smooth to a heavily folded surface. We develop a mathematical model that systematically analyzes the evolution of nuclear shape and volume. Our analysis suggests that the pressure difference across the nuclear envelope, which is influenced by changes in cell volume and regulated by microtubules and actin filaments, is a major factor determining nuclear morphology. Our results show that physical and chemical properties of the extracellular microenvironment directly influence nuclear morphology and suggest that there is a direct link between the environment and gene regulation. These findings broaden our understanding of 3D nuclear architecture and provide new prospects in laminopathies and cellular mechanotransduction.

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