Biophysical Society Thematic Meeting

Mechanobiology of Disease

Poster Abstracts

32-POS

Board 32

Cytoskeleton-medicated Nuclear Mechanics : Mechanobiological Approach into the

Subcellular Nanomachinery

Dong-Hwee Kim

, Sun X. Sun

, Denis Wirtz

Korea University, Seoul, South Korea,

Johns Hopkins University, Baltimore, MD, USA,

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.