FYSCELL-BMB Seminar

Nuclear mechano-confinement induces geometry-dependent HP1α condensate alterations

Cells sense external physical cues through complex processes involving signaling pathways, cytoskeletal dynamics, and transcriptional regulation to coordinate a cellular response. A key emerging principle underlying such mechanoresponses is the interplay between nuclear morphology, chromatin organization, and the dynamic behavior of nuclear bodies such as HP1α condensates. However, how mechanical alteration of the nucleus translates to specific responses in HP1α remains elusive. Here, applying super-resolution live-cell imaging, we report changes in the number, size and dynamics of HP1α nuclear condensates triggered by cell confinement below their resting nuclear diameter. Utilizing biophysical polymer models, we find that HP1α condensates become radially redistributed in the nucleus, dependent on the combined effect of HP1α's crosslinking activity and nuclear flattening. Moreover, HiC experiments and RNA sequencing reveal changes in 3D genome organization reflected in transcriptional changes before and after confinement over time. Taken together, these insights shed new light on the complex relationship between external forces and changes in nuclear shape and chromatin organization in cell mechanoreception.