Many cell types respond to applied force by altering gene and protein expression, but the mechanisms of this response have not been fully elucidated. Endothelial cells line blood vessels and respond to shear stress. Osteocytes are present in bone and respond to compression. We examined reorganization of genes in the nucleus of HeLa and HUVEC (endothelial) cells under shear stress and in HeLa and SAOS-2 (osteogenic) cells under compression by tracking fluorescent intranuclear markers. By studying large scale nuclear response under physiological levels of shear stress and compression, we are able to show that there is both a shear stress and compression induced change in nuclear reorganization. We observe a shift in nuclear response to force at ~30 minutes after the application of forces from increased random reorganization to a directed reorganization. Also, we observe that nuclei stiffened by overexpressing a mutant nuclear structural protein, progerin, show little response to shear, potentially from altered mechanotransductive response. Although not gene specific, these large scale rheological responses across the nucleus suggest that there is nuclear reorganization that could correspond to substantial changes in gene expression.