Mechanical Properties of the Cell Nucleus with Implications in Development, Disease and Aging

The sequencing of the human genome has provided a wealth of scientific information, but this information is limited by the poor understanding of the mechanisms which control gene expression. 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. Using spectrocopy, 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.