Chromatin-lamina interactions regulate gene activity by forming lamina-associated domains (LADs), which contribute to cellular identity through gene repression. However, the strength of these interactions and their responsiveness to environmental cues remain unclear. Here, we develop a theoretical framework to predict LAD morphology in human mesenchymal stem cells (MSCs), whose differentiation potential depends on the stiffness of the microenvironment. Our model integrates chromatin-lamina interactions with histone modifications, revealing a bimodal distribution of chromatin-lamina affinity shaped by nuclear heterogeneities such as nuclear pores. We predict that contractility-driven translocation of histone deacetylase 3 (HDAC3) enhances chromatin-lamina affinity, leading to LAD thickening on soft substrates-a prediction validated through imaging and functional perturbations. Notably, in tendinosis, a condition marked by collagen degeneration and tissue softening, LAD thickening mirrors the behavior of MSCs on soft substrates, highlighting how microenvironmental mechanics influence genome organization and stem cell fate.