Revealing the biophysics of lamina-associated domain formation by integrating theoretical modeling and high-resolution imaging
Year: 2025
Type: article
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.
Source: Nature Communications
Authors: Monika Dhankhar, Zixian Guo, Aayush Kant, Ramin Basir, Rohit Joshi, Vinayak Vinayak, Su Chin Heo, Robert L. Mauck, Melike Lakadamyali, Vivek B. Shenoy
Institutions: University of Pennsylvania, Philadelphia VA Medical Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, U.S. Department of Health and Human Services, National Institutes of Health, Materials Research Science and Engineering Center, Harvard University, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Biomedical Imaging and Bioengineering, Division of Materials Research, Division of Civil, Mechanical and Manufacturing Innovation
Awards: G1013684226, G1051554911, G155958390, Materials Research Science and Engineering Center, Pathological consequences of altered tissue mechanics in fibrosis, G2361442177, G2407097552, G2567800894, G2567842326, G3200575684, G342638498, G3740382785, G4212146726, G5462003112, G5743373210, Integration of elasticity, viscosity, and plasticity in cellular mechanosensing, G643866923, G6994470052, Mechanical determinants of organ-selective metastatic colonization, dormancy and outgrowth, An integrated approach to melanoma metastasis and therapy resistance: effects of age-related changes in the ECM and the biomechanics of the skin, G7947965700, Collaborative Research: DMS/NIGMS 1: Understanding genomic organization in the nucleus via biophysical modeling, super-resolution imaging, and data-efficient operator learning, G889968654, G9000060776, G9000095374, G9000106290
OpenAlex ID: W4413604380