(287b) Nuclear Rheology Associated with Early Development and Aging

The nucleus contains the genome and all of the regulatory proteins required for gene expression. However, gene expression changes drastically over the lifetime of an organism, particularly during early development and during phenotypic switches in a cellâ??s lifetime. In addition to containing the code for the cell, the genome within the nucleus is a complex, self-assembled polymeric structure with unique rheological properties. The genome of metazoan cells is surrounded by an intermediate filament network known as the nucleoskeleton, which also changes drastically in composition during development and aging. Using spectroscopy, imaging, micromanipulation and computational techniques, we measure the mechanics of the nucleoskeleton and the nuclear interior at various length scales. We are particularly interested in the role that force and cytokine treatment play in altering nuclear mechanics and gene expression in primary human cells. Motor activity from the cytoskeleton transduced through the nucleoskeleton impacts the driving force for nuclear and subnuclear movement, and altered chromatin condensation shifts the resistance and propagation of forces. We also quantify nuclear stiffness in a broad spectrum of cell types: cells with less regulated gene expression patterns, including stem cells and cancer cells, have much softer nuclei whereas aged cells have stiffer nuclei. While the mechanisms directing stiffness are still being elucidated, we have quantified dramatic downstream impacts of nuclear stiffness on cellular migration. Generally, nuclear architecture and mechanics impacts cell fate directly by altering cell stiffness and indirectly by modulating gene expression. These results have broad implications in cell biology, inhibition of cancer metastasis, and for applications in cellular therapies.