Heterogeneous force response of chromatin in isolated nuclei

A quantitative description of nuclear mechanics is crucial for understanding its role in force sensing within eukaryotic cells. Recent studies indicate that the chromatin within the nucleus cannot be treated as a homogeneous material. To elucidate its material properties, we combine optical tweezers manipulation of isolated nuclei with multi-color fluorescence imaging of lamin and chromatin to map the response of nuclei to local deformations. Force spectroscopy reveals nuclear strain stiffening and an exponential force dependence, well described by a hierarchical chain model. Simultaneously, fluorescence data show a higher compliance of chromatin compared to the nuclear envelope at strains <30%. Micrococcal nuclease (MNase) digestion of chromatin results in nuclear softening and can be captured by our model. Additionally, we observe stretching responses showing a lipid tether signature, suggesting that these tethers originate from the nuclear membrane. Our combined approach allows us to elucidate the nuclear force response while mapping the deformation of lamin, (eu)chromatin, and membrane.