Revealing the biophysics of lamina-associated domain formation by integrating theoretical modeling and high-resolution imaging

Monika Dhankhar, Zixian Guo, Aayush Kant, Ramin Basir, Rohit Joshi, Vinayak Vinayak, Su Chin Heo, Robert L. Mauck, Melike Lakadamyali and Vivek B. Shenoy ()
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Monika Dhankhar: University of Pennsylvania
Zixian Guo: University of Pennsylvania
Aayush Kant: University of Pennsylvania
Ramin Basir: University of Pennsylvania
Rohit Joshi: University of Pennsylvania
Vinayak Vinayak: University of Pennsylvania
Su Chin Heo: University of Pennsylvania
Robert L. Mauck: University of Pennsylvania
Melike Lakadamyali: University of Pennsylvania
Vivek B. Shenoy: University of Pennsylvania

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63244-1

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