Physico-chemical signals from the extracellular matrix impinge on cellular geometry resulting in altered functional nuclear landscape and gene expression. While these alterations regulate diverse biological processes including stem-cell differentiation, developmental genetic programs and cellular homeostasis; the biophysical principles underlying such control systems are unclear. Using a multidisciplinary approach, combining high resolution live-cell imaging, micro-patterned substrates and single-cell mechanics experiments, our laboratory investigates the biophysical principles underlying the coupling between nuclear mechanics and genome regulation. I will describe our ongoing work that provides modular links between cellular geometry and nuclear mechanics and its impact on 3D organization of chromosomes and gene expression.