Significance – Many human disease present alterations in nuclear mechanics and morphology across the human disease spectrum (heart disease, muscular dystrophy, aging, cancer, and more). Specifically, abnormal shape of the cell nucleus has been used for over 80 years (since the Pap test in 1930s) for the diagnosis and prognosis of cancer. However, the mechanical basis of this abnormal nuclear morphology remains unknown. My first publication provided the ability to separate the contributions of the two major mechanical components, chromatin and lamins. With the ability to only modulate chromatin rigidity and compaction via histone modification state (eu/heterochromatin), I investigated the contribution of chromatin to nuclear morphology. My findings provide strong evidence that chromatin and not lamins dictate nuclear morphology.

Results – My paper Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins shows that decreased chromatin-based nuclear rigidity by increasing decompact euchromatin or decreasing compact heterochromatin results in an increase in nuclear blebbing. Furthermore, while it was previously believed that nuclear blebbing was only due to alterations of lamins, this paper reveals that the altering the amount and distribution of lamin A or B is not necessary for bleb formation. Finally, this paper reveals that lamin mutants that display nuclear blebbing also display decreased heterochromatin, which alone could account for nuclear blebbing and abnormal morphology. In fact, rescuing levels of heterochromatin alone (which increased chromatin-based nuclear rigidity)  is sufficient to decrease nuclear blebbing in lamin B1 null cells and rescue nuclear morphology in model and patient cell lines of aging disease Hutchinson-Gilford Progeria syndrome, caused by mutant lamin A. Thus, histone modification state (eu/heterochromatin) determines nuclear rigidity which in turn dictates nuclear morphology maintenance in a manner that is independent of lamin mutation, amount, distribution, or mechanical contribution.

Video – Human HT1080 cells treated with histone deacetylase inhibitor (HDACi) VPA to decompact chromatin exhibit nuclear blebbing. Nuclear rupture is tracked by NLS-GFP, which leaves the nucleus upon rupture, but does reacculmulate upon healing. Nuclear shape is tracked by H2B-RFP (magenta). This video represents 4 hours with an image taken every 10 minutes and played at 2 frames per second.