Non-Muscle Sarcomeres Sense Rigidity and Generate High Forces

The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that uncoupling of microtubules from integrin adhesions by depletion or displacement of KANK family proteins connecting the adhesion protein talin with microtubule tips led to disruption of podosomes and augmentation of focal adhesions, similarly to total disruption of microtubules. Both microtubule uncoupling from adhesions and total microtubule disruption bring about a massive assembly of myosin-IIA filaments, whilst a burst of microtubule polymerization led to a transient disassembly of myosin-IIA filaments. Myosin-IIA filaments are indispensable for microtubule-dependent regulation of integrin-mediated adhesions. The myosin-IIA filament assembly depends on Rho activation by RhoGEF, GEF-H1, which is trapped by microtubules connected with integrin adhesions but released after their disconnection. Thus, microtubule capturing by integrin-mediated adhesions modulates the effect of microtubules on the actomyosin cytoskeleton. The actomyosin reorganization then remodels the adhesions, closing the regulatory loop. Geometric control of genome programs G.V.Shivashankar Mechanobiology Institute, National University of Singapore, Singapore & FIRC Institute of Molecular Oncology (IFOM), Milan, Italy [email protected] Cells integrate both biochemical and physical signals within the tissue microenvironment to maintain homeostasis. However, cell geometric constraints are highly heterogeneous and it is unclear how such heterogeneity in their shapes (and thus mechanics) affect the micro environmental regulation of genome programs. To address this we use micro patterned substrates to sculpt cell geometry and study its role in integrating micro environmental signals such as cytokines and tissue compression. In this talk, I will discuss an important layer of genome regulation resulting from the coupling between cell geometry and 3D organization of chromosomes. Collectively, our results show that geometric states of cells dictate micro environmental control of gene expression and sustained growth of cells on such geometrically confined substrates result in novel routes to nuclear reprogramming.