Role of nuclear ATPases in nuclear mechanics and cell migration through confined spaces: Opposite effects of BRG1 and cohesin.

Deformation of the nucleus often presents a barrier to cell migration through tight spaces, such as those encountered as cells move through tissues or across extracellular matrix barriers. Reorganization of the nucleus to allow its passage through spaces much smaller than its resting diameter requires forces generated by the cytoskeleton, as well as active reorganization within the nucleus driven by ATPases that cross-link or move chromatin. Here, we show that two different nuclear ATPases, the BRG1/BRM motor of the BAF or SWI/SNF complex and the bifunctional cross-linking and loop extruding complex, cohesin, have opposite effects on the stiffness of isolated nuclei. Inhibition of BRG1/BRM stiffens the nucleus, and inhibiting cohesin softens the nucleus in karyoplasts derived from multiple cell types, including four different cancer cells, fibroblasts, and mesenchymal stem cells. The effects on isolated nuclear stiffness coincide with the effects of these ATPases on the ability of cells to migrate through tight spaces. Stiffening the nucleus inhibits single-cell migration through micron-sized pores and the outward migration of tumor cell spheroids into a surrounding collagen matrix. Softening the nucleus by inhibiting cohesin has the opposite effect: it enhances single-cell migration through pores, at least for some cell types, and facilitates the outgrowth of cells from a tumor cell spheroid into the surrounding matrix. These results emphasize the importance of ATP-dependent chromatin remodeling for shaping the mechanical properties of the nucleus and the way that it deforms in response to externally generated stresses.