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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月25日

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  • Monika Dhankhar,
  • Zixian Guo,
  • Aayush Kant,
  • Ramin Basir,
  • Rohit Joshi,
  • Vinayak Vinayak,
  • Su Chin Heo,
  • Robert L. Mauck,
  • Melike Lakadamyali,
  • Vivek B. Shenoy

摘要

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.