  The nuclear morphology of eukaryotic cells is determined by the interplay
between the lamina forming the nuclear skeleton, the chromatin inside the
nucleus and the coupling with the cytoskeleton. Nuclear alterations are often
associated with pathological conditions as in the Hutchinson-Gilford progeria
syndrome (HGPS) where a mutation in the lamin A gene yields an altered form of
the protein, named progerin, and an aberrant nuclear shape. Here, we introduce
an inducible cellular model of HGPS in HeLa cells where increased progerin
expression leads to alterations in the coupling of the lamin shell with
cytoskeletal/chromatin tethers as well as with Polycomb-group (PcG) proteins.
Furthermore, our experiments show that progerin expression leads to enhanced
nuclear shape fluctuations in response to cytoskeletal activity. To interpret
the experimental results, we introduce a computational model of the cell
nucleus that includes explicitly chromatin fibers, the nuclear shell and the
coupling with the cytoskeleton. The model allows us to investigate how the
geometrical organization of chromatin-lamin tether affects nuclear morphology
and shape fluctuations. In sum, our findings highlight the crucial role played
by lamin-chromatin and lamin-cytoskeletal alterations in determining nuclear
shape morphology and in affecting cellular functions and gene regulation.
