Cells can mediate tissue maintenance and growth through mechanotransduction, i.e. the translation of mechanical forces into biochemical signals. Proteins at the nuclear envelope such as nuclear lamins and the LINC complex connect cytoplasmic mechanical forces directly to the genome with the potential to influence genome organization and transcriptional regulation. While it is known that these nuclear envelope proteins activate mechanosensitive genes, the distinct mechanisms are not yet clear due to the inability to parse out nuclear mechanisms with cytoplasmic signaling. In this dissertation, I sought to address this gap by inducing mechanical stress to fibroblasts and mapping genome-wide changes in transcription, chromosomal organization, and chromatin accessibility temporally and at high resolution. The assays presented herein provided detailed information on the genome-wide consequences of mechanical stress to the cell and served as a foundation to systematically assess the role of nuclear envelope proteins in mechanosensitive gene expression.