Dhankhar, M. | Search bioRxiv

bioRxiv2026

Recursive feedback between Piezo1 conformation and membrane mechanics drives self-organization into finite clusters

Piezo1 is a major mechanosensitive ion channel through which cells convert physical force into calcium-dependent signaling programs. In living membranes, this conversion depends not only on channel activation, but also on whether Piezo1 channels remain dispersed, assemble into finite clusters, or concentrate at sites where receptor signaling and mechanical forces reorganize the membrane. How single-channel force sensing is amplified into these collective spatial states remains unknown. Here we identify a membrane-feedback mechanism that converts single-channel mechanosensing into self-organized Piezo1 clusters. Coupling channel shape to membrane-cortex elasticity reveals that neighboring channels relax shared deformation fields, generating an effective interaction with short-range attraction opposed by longer-range repulsion. As channel density or membrane tension increases, this balanced interaction shifts Piezo1 from dispersed channels into mesoscale finite clusters. Brownian-dynamics simulations reproduce experimentally observed Piezo1 cluster geometries and swelling-induced cluster growth, while comparisons across distinct cellular systems place Piezo1 organization within a common density-tension framework. Applying the same mechanism to LPS-activated macrophages shows how receptor-induced membrane reorganization locally concentrates Piezo1 above the clustering threshold. Overall, these results recast Piezo1 mechanotransduction from isolated-channel force sensing to a membrane-driven self-organization process that spatially biases force-dependent calcium signaling within cells.

biophysics↗

bioRxiv2024

Revealing the Biophysics of Lamina-Associated Domain Formation by Integrating Theoretical Modeling and High-Resolution Imaging

The interactions between chromatin and the nuclear lamina orchestrate cell type-specific gene activity by forming lamina-associated domains (LADs) which preserve cellular characteristics through gene repression. However, unlike the interactions between chromatin segments, the strength of chromatin-lamina interactions and their dependence on cellular environment are not well understood. Here, we develop a theory to predict the size and shape of peripheral heterochromatin domains by considering the energetics of chromatin-chromatin interactions, the affinity between chromatin and the nuclear lamina and the kinetics of methylation and acetylation9in human mesenchymal stem cells (hMSCs). Through the analysis of super-resolution images of peripheral heterochromatin domains using this theoretical framework, we determine the nuclear lamina-wide distribution of chromatin-lamina affinities. We find that the extracted affinity is highly spatially heterogeneous and shows a bimodal distribution, indicating regions along the lamina with strong chromatin binding and those exhibiting vanishing chromatin affinity interspersed with some regions exhibiting a relatively diminished chromatin interactions, in line with the presence of structures such as nuclear pores. Exploring the role of environmental cues on peripheral chromatin, we find that LAD thickness increases when hMSCs are cultured on a softer substrate, in correlation with contractility-dependent translocation of histone deacetylase 3 (HDAC3) from the cytosol to the nucleus. In soft microenvironments, chromatin becomes sequestered at the nuclear lamina, likely due to the interactions of HDAC3 with the chromatin anchoring protein LAP2{beta} ,increasing chromatin-lamina affinity, as well as elevated levels of the intranuclear histone methylation. Our findings are further corroborated by pharmacological interventions that inhibit contractility, as well as by manipulating methylation levels using epigenetic drugs. Notably, in the context of tendinosis, a chronic condition characterized by collagen degeneration, we observed a similar increase in the thickness of peripheral chromatin akin to that of cells cultured on soft substrates consistent with theoretical predictions. Our findings underscore the pivotal role of the microenvironment in shaping genome organization and highlight its relevance in pathological conditions.

biophysics↗